Multicomponent synthesis of fluorinated organic compounds using novel lewis acid catalysis and related chemistry

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Content MULTICOMPONENT SYNTHESIS OF FLUORINATED ORGANIC COMPOUNDS

USING NOVEL LEWIS ACID CATALYSIS AND RELATED CHEMISTRY

by

Clement Do

A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)

August 2010

Copyright 2010 Clement Do
ii

DEDICATION

to

My Beloved Dad and Mom
iii
ACKNOWLEDGMENTS

I heartily thank Prof. G. K. Surya Prakash, my mentor for giving me the great
opportunity to work in his lab for the past 5 years. I am immensely grateful to him for
imparting in me great ideas in Chemistry from his unfathomable knowledge. He has been
not only a wonderful teacher and supervisor to me but also a great human being. This
dissertation would not have been possible without his endless guidance, support and
freedom in chemistry that he grants us. I would also like to thank Prof. George A. Olah
for his constant inspiration and motivation, and especially for his profound knowledge in
both chemistry and philosophy. They inspire me to strive for higher levels of excellence
as both a chemist and as a human being.
I would also like to thank Dr. Thomas Mathew for his help and assistance in my
research program especially in chemistry and lab techniques. I have learned a lot from
him in both chemistry and as a human being. My special thanks to Dr. Chiradeep Panja
for all the lab techniques that he taught me. He did not hesitate to help whenever his help
was needed. I also thank Prof. Golam Rasul for all his help and support in my research
program especially in computational studies. I am very grateful to Mr. Fang Wang, who
helped me to finish two of my projects with his expertise and insights in organofluorine
chemistry. I would also like to extend my gratitude to Dr. Habiba Vaghoo and Dr. Kevin
Glinton for constant support throughout the program. In addition, I am thankful to Dr.
Alain Goeppert for his help and cooperation, knowledge and williness to help. There are
many other individuals in Olah-Prakash group who provided support and guidance during
my graduate studies. In this regard, I would like to thank Dr. Somesh Ganesh, Dr.
Fabrizio Pertusati, Dr. Rehana Ismail, Dr. Sujith Chacko and Dr. Farzaneh Paknia. My
iv
thanks are also due to other members including Dr. Sergio Meth, Dr. Patrice Batamack,
Dr. Federico Viva, Dr. Parag Jog, Dr. Miklos Czaun, Dr. Kiah Smith, Anton, J-P, Hema,
Charlie, Inessa, Nan, Arjun and all of the present and past members of the group.
I would also take this opportunity to thank all the undergraduates who have
worked with me specially, Balyn, Hubert, Tito and Tisa. Without their active help it
would have been impossible for me to finish some of my projects in reasonable time.
I thank my thesis committee members Professor Katherine Shing, Professor Thieo
E. Hogen-Esch and late Professor Robet Bau for their guidance and helpful discussions.
As well, I would like to express my gratitude to Prof. Clay C. C. Wang and Prof. Richard
B. Kaner for their constant encouragement.
Thanks are also due to other staff members of the Chemistry Department and
Loker Hydrocarbon Institute, especially Michele Dea, Heather Connor, Jessy May,
Carole Philips, Ralph Pan and David Hunter for their kind support. Mr. Allan Kershaw
and Mr. Jim Merit are also acknowledged for their technical help with NMR
specrometers and glass blowing.

v
TABLE OF CONTENTS

DEDICATION ii

ACKNOWLEDGMENTS iii

LIST OF TABLES viii

LIST OF FIGURES x

LIST OF SCHEMES xii

ABSTRACT xiv

1 Chapter 1: Introduction .............................................................................................1
1.1 Chapter 1: General Overview of Lewis Acids ......................................................1
1.1.1 The Need for Green Lewis Acid Catalyst ..................................................6
1.1.2 Trimethylsilyl Trifluoromethanesulfonate (TMSOTf) as a Strong
Lewis Acid Catalyst ............................................................................... 10
1.1.3 Significance of Organofluorine compounds ............................................ 15
1.2 Chapter 1: Aim and Scope of the Present Work .................................................. 20
1.3 Chapter 1: References ........................................................................................ 22

2 Chapter 2: Gallium(III) Triflate Catalyzed Direct Reductive Amination of
Aldehydes .................................................................................................................. 27
2.1 Chapter 2: Introduction ...................................................................................... 27
2.2 Chapter 2: Results and Discussion ...................................................................... 29
2.3 Chapter 2: Conclusion ........................................................................................ 36
2.4 Chapter 2: Experimental ..................................................................................... 36
2.4.1 General ................................................................................................... 36
2.4.2 General Procedure for Ga(OTf)
3
-Catalyzed Reductive Amination of
Aldehydes .............................................................................................. 37
2.4.3 Spectral Data .......................................................................................... 37
2.5 Chapter 2: Representative Spectra ...................................................................... 42
2.6 Chapter 2: References ........................................................................................ 46

3 Chapter 3: Reduction of Carbonyl to Methylene: Me
2
SiHCl-Ga(OTf)
3
as an
Efficient Reductant System ...................................................................................... 49
3.1 Chapter 3: Introduction ...................................................................................... 49
3.2 Chapter 3: Results and Discussion ...................................................................... 50
3.3 Chapter 3: Conclusion ........................................................................................ 57
vi
3.4 Chapter 3: Experimental ..................................................................................... 57
3.4.1 General ................................................................................................... 57
3.4.2 General Procedure for Ga(OTf)
3
catalyzed carbonyl
defunctionalization of ketones with Me
2
SiHCl........................................ 58
3.4.3 Spectral Data .......................................................................................... 58
3.5 Chapter 3: Representative Spectra ...................................................................... 59
3.6 Chapter 3: References ........................................................................................ 61

4 Chapter 4: Trimethylsilyl Trifluoromethanesulfonate as a Metal-Free,
Homogeneous and Strong Lewis Acid Catalyst for Efficient One-Pot
Synthesis of α-Aminonitriles and Their Fluorinated Analogues ............................. 64
4.1 Chapter 4: Introduction ...................................................................................... 64
4.2 Chapter 4: Results and Discussion ...................................................................... 65
4.3 Chapter 4: Conclusion ........................................................................................ 71
4.4 Chapter 4: Experimental ..................................................................................... 71
4.4.1 Materials and Methods ........................................................................... 71
4.4.2 General Procedure for the Strecker Reaction of Aldehydes
and Ketones ............................................................................................ 72
4.5 Chapter 4: References ........................................................................................ 73

5 Chapter 5: Efficient One-Pot Synthesis of Novel Fluorinated Heterocycles
Using Trimethylsilyl Trifluoromethanesulfonate as a Metal-Free
Homogeneous Lewis Acid Catalyst .......................................................................... 79
5.1 Chapter 5: Introduction ...................................................................................... 79
5.2 Chapter 5: Results and Discussion ...................................................................... 81
5.2.1 Synthesis of Fluorinated Benzimidazolines, Thiazolines,
Oxazolines and Oxazinones .................................................................... 81
5.2.2 Synthesis of 1,2,3,4-tetrahydroquinazolines, 4H-3,1-benzoxazines
and 3,1-benzoxathiin-4-ones ................................................................... 91
5.3 Chapter 5: Conclusion ........................................................................................ 98
5.4.1 General ................................................................................................... 98
5.4.2 General procedure for the TMSOTf catalyzed cyclization-
condensation........................................................................................... 99
5.4.3 Spectra Data ........................................................................................... 99
5.5 Chapter 5: References ...................................................................................... 105

6 Chapter 6: Cyclodehydration of Fluorinated Diols Using the Mitsunobu
Reaction: Highly Efficient Synthesis of Trifluoromethylated Cyclic Ethers ........ 110
6.1 Chapter 6: Introduction .................................................................................... 110
6.2 Chapter 6: Results and Discussion .................................................................... 112
6.3 Chapter 6: Conclusion ...................................................................................... 120
6.4 Chapter 6: Experimental ................................................................................... 120
vii
6.4.1 General ................................................................................................. 120
6.4.2 Preparation of cis-3,3,3-Trifluoro-1,2-diphenylpopane-1,2-diol (1a) .... 121
6.4.3 Typical Procedure for the Preparation of Fluorinated Diols 1d-f
and 1h-l (Table 6.2, Entries d-f, h-l); 1,1,1-Trifluoro-
2-[2-(hydroxymethyl)phenyl]propan-2-ol (1e) ...................................... 122
6.4.4 General Procedure for the Preparation of 1b and 1c .............................. 123
6.4.5 General Procedure for the Preparation of 1g and 1h .............................. 123
6.4.6 Typical Experimental Procedure for the Mitsunobu
Cyclodehydration Reaction ................................................................... 124
6.4.7 Spectral Data ........................................................................................ 124
6.5 Chapter 6: Representative Spectra .................................................................... 133
6.6 Chapter 6: References ...................................................................................... 141

7 Chapter 7: Organocatalytic Stereoselective Conjugate Addition of
-Fluoro- -nitro-phenyl sulfonyl methane to -Nitroolefins: The
Construction of Fluorine-bearing Chiral Carbon Center ..................................... 145
7.1 Chapter 7: Introduction .................................................................................... 145
7.2 Chapter 7: Results and Discussion .................................................................... 146
7.3 Chapter 7: Conclusion ...................................................................................... 159
7.4 Chapter 7: Experimental ................................................................................... 160
7.4.1 General ................................................................................................. 160
7.4.2 Typical procedure for the preparation of
(chloro(nitro)methylsulfonyl)benzene ................................................... 161
7.4.3 Typical procedure for catalytic conjugate addition of
α-fluoro-α-nitro(phenylsulfonyl)methane to nitroolefins ....................... 161
7.4.4 Typical procedure for catalytic enantioselective conjugate addition
of α-fluoro-α-nitro(phenylsulfonyl)methane to nitroolefins ................... 162
7.4.5 Spectral Data ........................................................................................ 162
7.6 Chpater 7: References ...................................................................................... 166

BIBLIOGRAPHY………………………………………………………………………168

viii
LIST OF TABLES
Table 1.1 Examples of Lewis acids ..........................................................................3
Table 1.2 Classification of some common Lewis acids and bases .............................6
Table 2.1 Screening of organosilane reductants for gallium triflate catalyzed
reductive amination of aldehydes ............................................................ 31
Table 2.2 Ga(OTf)
3
catalyzed reductive amination of aldehydes with
triethylsilane ........................................................................................... 32
Table 3.1 Screening of solvents and organosilane reductants for Ga(OTf)
3
catalyzed carbonyl defunctionalization reaction ...................................... 52
Table 3.2 Ga(OTf)
3
catalyzed carbonyl defunctionalization of ketones with
Me
2
SiHCl ............................................................................................... 54
Table 4.1 Strecker Reaction of Acetophenone and Aniline Catalyzed by
Trimethylsilyl Triflate and Various Metal Triflates ................................. 66
Table 4.2 TMSOTf-Catalyzed Strecker Reaction Using Different
Aldehydes/Ketones and Amines ............................................................. 68
Table 4.3 TMSOTf-Catalyzed Strecker Reaction of Mono-, Di-, and
Trifluoromethyl Ketones......................................................................... 70
Table 5.1 Reaction of 1,2-phenylenediamine with 1,1,1-trifluoroacetone using
various metal triflates and TMSOTf as the catalysts................................ 87
Table 5.2 Preparation of 2-fluoroalkyl benzimidazolines using TMSOTf as the
catalyst ................................................................................................... 89
Table 5.3 Preparation of fluorinated benzothiazolines, benzoxazolines and
dihydrobenzoxazinones using using TMSOTf as the catalyst .................. 90
Table 5.4a Preparation of fluorinated 1,2,3,4-tetrahydroquinazolines and 4H-3,l-
benzoxazines using TMSOTf as the catalyst ........................................... 92
Table 5.4b Preparation of fluorinated 2,3-dihydro-4(lH)-quinazolinones using
TMSOTf as the catalyst .......................................................................... 93
Table 5.5 Preparation of fluorinated 3,l-benzoxathiin-4-ones using TMSOTf
as the catalyst ......................................................................................... 94
Table 6.1 Optimization of the Mitsunobu Cyclodehydration Reaction .................. 113
ix
Table 6.2 The Mitsunobu Cyclodehydration of Fluorinated Diols ......................... 117
Table 7.1 Catalyst screening of asymmetric conjugate addition reaction of
FNSM to nitroolefins ............................................................................ 149
Table 7.2 Screening of reaction media and temperature ........................................ 150
Table 7.3 Organocatalyzed stereoselective conjugate addition between
FNSM and nitroolefins ......................................................................... 152
Table 7.4 Kinetic analysis of the conjugate addition of FNSM/ClNSM to
nitroolefins ........................................................................................... 153

x
LIST OF FIGURES
Figure 1.1 Common fluorinated drugs ..................................................................... 16
Figure 1.2 Chiral electrophilic fluorinating agents ................................................... 17
Figure 1.3 Fluorinated drugs prepared by enantioselective electrophilic
fluorination ............................................................................................. 17
Figure 1.4 Fluorinated ethers as agrochemicals ........................................................ 19
Figure 1.5 Fluorinated ethers as pharmaceuticals ..................................................... 19
Figure 2.1
1
H NMR Spectrum of 3l ......................................................................... 42
Figure 2.2
13
C NMR Spectrum of 3l ........................................................................ 43
Figure 2.3
1
H NMR Spectrum of 3o ........................................................................ 44
Figure 2.4
13
C NMR Spectrum of 3o ....................................................................... 45
Figure 3.1
1
H NMR Spectrum of 2i ......................................................................... 59
Figure 3.2
13
C NMR Spectrum of 2i ........................................................................ 60
Figure 6.1 The NMR analysis of 3,3,3-trifluoro-1,2-diphenylpropane-
1,2-diol (1a) ......................................................................................... 118
Figure 6.2
1
H NMR Spectrum of 1a ...................................................................... 133
Figure 6.3
19
F NMR Spectrum of 1a ...................................................................... 134
Figure 6.4
1
H-
1
H COSY Spectrum of 1a................................................................ 135
Figure 6.5 NOESY Spectrum of 1a ....................................................................... 136
Figure 6.6
1
H-
19
F HOESY Spectrum of 1a ............................................................ 137
Figure 6.7
1
H NMR Spectrum of 2a ...................................................................... 138
Figure 6.8
1
H-
1
H COSY Spectrum of 2a................................................................ 139
Figure 6.9 NOESY Spectrum of 2a ....................................................................... 140
Figure 7.1 Bifunctional organocatalysts ................................................................. 147
Figure 7.2 Plot of [FNSM]
-1
/[ClNSM]
-1
versus reaction time ................................. 154
xi
Figure 7.3 Thermodynamics of deprotonation of FNSM and ClNSM and
the optimized geometris of ClNSM and FNSM anions .......................... 156
Figure 7.4 Interconversion between (R)-FNSM and (S)-FNSM (The pathways
from TS
1
and TS
3
to (S)-FNSM are omitted for clarity) ........................ 157
Figure 7.5 Structural changes in the interconversion between (R)-
and (S)-FNSM ...................................................................................... 159

xii
LIST OF SCHEMES
Scheme 1.1 The formation of an adduct from Lewis acid A and Lewis base B .............2
Scheme 1.2 Synthesis of silicon Lewis acids ............................................................. 11
Scheme 1.3 General mechanistic pathways of organosilicon Lewis acid .................... 12
Scheme 1.4 General reaction mechanism of TMSOTf with acetal or acetal-like
compounds ............................................................................................. 12
Scheme 1.5 General mechanism of TMSOTf catalyzed reactions of carbonyl
compounds ............................................................................................. 13
Scheme 1.6 Principles of catalytic action of TMSOTf................................................ 14
Scheme 1.7 Activation of C=N bond ......................................................................... 14
Scheme 1.8 Reactions of imines with TMSOTf ......................................................... 14
Scheme 2.1 Gallium triflate catalyzed reductive amination of aldehydes ................... 30
Scheme 2.2 Proposed mechanism of the Ga(OTf)
3
catalyzed direct reductive
amination ............................................................................................... 35
Scheme 3.1 Ga(OTf)
3
catalyzed carbonyl defunctionalization reaction....................... 51
Scheme 3.2 Proposed reaction pathway ..................................................................... 56
Scheme 4.1 TMSOTf-catalyzed Strecker reaction using aldehydes/ketones and
amines .................................................................................................... 67
Scheme 4.2 TMSOTf-catalyzed Strecker reaction of fluorinated ketones ................... 69
Scheme 5.1 Reactions of benzaldehyde and ketones with 1,2–phenylenediamines ..... 82
Scheme 5.2 Synthesis of fluorinated benzimidazolines from fluorinated alkynyl
carboxylic acids and vicinal-diamines ..................................................... 83
Scheme 5.3 Mechanism of the formation of five and seven membered ring ............... 85
Scheme 5.4 Condensation of ketones with o-amimoarenes using TMSOTf as
catalyst ................................................................................................... 87
Scheme 5.5 Syntheses of 1,2,3,4-tetrahydroquinazolines 8b, 2,3-dihydro-4(1H)-
quinazolinones 8c, and 4H-3,1-benzoxazines 8d using TMSOTf as
the catalyst ............................................................................................. 91
xiii
Scheme 5.6 Synthesis of 3,1-benzoxathiin-4-ones 12 using TMSOTf as the
catalyst ................................................................................................... 93
Scheme 5.7 Condensation of ketones with 13, 16 and 18 using TMSOTf as
catalyst ................................................................................................... 95
Scheme 5.8 Modified mechanism .............................................................................. 97
Scheme 6.1 Synthesis of trifluoromethylated cyclic ethers via the Mitsunobu
cyclodehydration .................................................................................. 112
Scheme 6.2 Proposed reaction pathway ................................................................... 120
Scheme 6.3 Preparation of cis-3,3,3-Trifluoro-1,2-diphenylpopane-1,2-diol ............ 121
Scheme 6.4 Typical Procedure for the Preparation of Fluorinated Diols 1d-f
and 1h-l ................................................................................................ 123
Scheme 6.5 General Procedure for compound 1b and 1c ......................................... 123
Scheme 6.6 General Procedure for compound 1g and 1h ......................................... 124

xiv
ABSTRACT
This dissertation focuses on the development of new methodologies for the
synthesis of both fluorinated and non-fluorinated biologically important molecules via the
use of green Lewis acid catalysts. It also describes the syntheses of fluorinated cyclic
ethers via Mitsunobu conditions. In addition, the stereoselective construction of fluorine
bearing chiral carbon centers have also been explored.
In chapter 1, a general overview of Lewis Acids with the emphasis on TMSOTf
catalyzed reactions are described. The need for a green Lewis acid catalyst and the
significance of fluorine containing molecules are also mentioned.
In chapter 2, the direct reductive amination of aldehydes in the presence of silanes
using Ga(OTf)
3
as a catalyst has been disclosed. Mild conditions, easy work-up and high
purity of products with excellent yields are the major advantages of this method.
In chapter 3, a versatile carbonyl defunctionalization system has been achieved
using a water tolerant, recyclable, catalytic Ga(OTf)
3
/Me
2
SiHCl system. Both aromatic
and aliphatic ketones were effectively reduced to the corresponding methylene products
with high functional groups tolerance, under very mild conditions in a relatively short
time with good to excellent yield.
In chapter 4, the one-pot three-component Strecker reaction of ketones/fluorinated
ketones for the preparation of α-aminonitriles/fluorinated α-aminonitriles has been
achieved using trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a metal-free strong
Lewis acid catalyst. These reactions are simple and clean, giving the products in high
yield and high purity.
xv
In chapter 5, the one-pot synthesis of biologically active fluorinated heterocycles
such as benzimidazolines, benzothiazolines, benzoxazolines, dihydrobenzoxazinones,
1,2,3,4-tetrahydroquinazolines, 4H-3,1-benzoxazines and 3,1-benzoxathiin-4-ones using
TMSOTf as a metal free catalyst has been disclosed.
In chapter 6, synthesis of trifluoromethylated cyclic ethers has been achieved via
the Mitsunobu cyclodehydration of fluorinated diols with high efficacy. The
methodology is found to be widely applicable to the synthesis of cyclic ethers with
varying ring size (3–7) from fluorinated diols of differing acidities and steric demands.
Cyclic ethers with considerable ring strain can be achieved in moderate yields by this
protocol. The methodology is suitable for both primary and secondary alcohols as well as
benzylic and aliphatic alcohols as electrophiles to afford the corresponding products in
moderate to good yields.
In chapter 7, both synthetic and theoretical aspects of the asymmetric
organocatalyst mediated conjugate addition of FNSM to nitro-olefins for the construction
of fluorinated stereogenic center has been explored.

1
1 Chapter 1: Introduction

1.1 Chapter 1: General Overview of Lewis Acids
The Lewis theory of acids and bases and their electron dot structure
representations are well known to students of chemistry. Indeed, one of the most common
and best-studied area in chemical reactions is the Lewis acid catalysis,
1-4
which deals
with various organic functional group transformations in the presence of Lewis acids.
5

The Lewis acid and base theory was named after the American physical chemist, Gilbert
Newton Lewis. Lewis is also known for his book Thermodynamics and the Free Energy
of Chemical Substances
6
and was the first to purify and characterize a sample of heavy
water in 1933.
7
Valence and the Structure of Atoms and Moleules
8
is another famous
book that he has written, in which he formulated the concept of the covalent bond, a
shared pair of electrons, and proposed the famous octet rule. These ideas on chemical
bonding were expanded upon by Irving Langmuir and inspired the studies on the nature
of chemical bond by Linus Pauling. His contributions to thermodynamics and bonding
theory laid the foundations for a better understanding of chemical bonds and particularly
reaction mechanisms.
2
It is also in this book that Lewis proposed his general definition of
acids and bases using electron pair sharing concept.
9
According to Lewis,
8,10
acids are
electron-pair acceptors and bases are electron-pair donors.
The reaction between an electron-deficient atom of Lewis acid A and the
unshared electron pair of Lewis base B result in the formation of what is now usually
called an adduct (coordination or addition compound) A-B, held together by a coordinate
covalent bond (or dative bond or dipolar bond) (Scheme 1.1).
9

2
A B + A-B

Scheme 1.1 The formation of an adduct from Lewis acid A and Lewis base B

In contrast to Brønsted definition where an acid is a proton donor, the Lewis
definition is much more general. Proton being a Lewis acid, accepts an electron pair into
its empty 1s atomic orbital; it follows that all Brønsted bases are Lewis bases and all
Brønsted acids are also Lewis acids because all Brønsted acids are protons donors. The
definition of Lewis covers almost every acid-base processes, which includes heterolysis,
coordination, solvation, complexation, hydrogen-bond formation, halogen-bond
formation and electrophilic and nucleophilic reactions.
9
Therefore, it is not surprising that
the discussions of Lewis acidity and basicity can be found in almost every general,
organic or inorganic chemistry textbooks. Some common Lewis acids are listed in (Table
1.1).

3
Table 1.1 Examples of Lewis acids
9

While the quantitative study for the strength of Brønsted acids are well
established, no universal order for the strength of Lewis acidity exists at the present time
even though several attempts have been made. In the Brønsted definition, the proton is
used as the reference to determine the acid dissociation constant either in water (pH) or

Metals: M

Cations
Proton: H
+

Metallic: M
n+

Organometallic: CH
3
Hg
+

Halogens: I
+

Carbocations: CH
3
+

Covalent metal halides, hydrides or alkyls: MX
n
, MH
n
, MR
n

Group 4: TiCl
4

Group 8: FeCl
3

Group 12: ZnCl
2
, CdI
2
, HgCl
2

Group 13: BF
3
, BCl
3
, BH
3
, BMe
3

AlCl
3
, AlMe
3

GaCl
3
, GaH
3
, GaMe
3

Group 14: SnCl
4

Group 15: SbCl
3
, SbCl
5

Halogen-bond donors
Dihalogens: I
2
, Br
2
, Cl
2

Interhalogens: ICl, IBr, ClF, BrCl
Organic halogens: IC≡N, ICF
3
, IC≡CR

Hydrogen-bond donors (Bronsted acids)
OH: RCOOH, ArOH, ROH, H
2
O
NH: RCONH
2
, ArNH
2
, HNCS
CH: CHCl
3
, RC≡CH
SH: ArSH
XH: HF, HCl

π Acceptors
SO
3

4
non-aqueous system (-H
0
) by potentiometric titration, spectrophotometric or NMR
measurements so that the strength of several thousand Brønsted acids can be measured
explicitly. In contrast, there is no universally valid description of Lewis acid strength,
because Lewis acid strength depends on the specific Lewis base used for reference and
there is no single reference that describes everything. Consequently, there are potentially
many acidity scales for references.
9
Nevertheless, the affinities of Lewis acids and bases
can be judged from the concept of hard and soft acid and bases (HSAB) introduced by
Pearson in 1963.
11-12
The HSAB principle states that soft acids tend to react faster and
form stronger bonds with soft bases, whereas hard acids tend to react faster and form
stronger bonds with hard bases, when all other factors are similar. According to Pearson,
hard and soft acids and bases are defined as follows:
5,9,11,13-14

Hard acids: electron-pair acceptors, in which the acceptor atoms have high
positive charge, small size, low polarizability and are associated with lowest-unoccupied
molecular orbitals (LUMO) of high energy.
Hard bases: electron-pair donors, in which the donor atoms have low
polarizability, high electronegativity, and are associated with highest-occupied molecular
orbitals (HOMO) of low energy.
Soft acids: electron-pair acceptors, in which the acceptor atoms have low positive
charge, large size, high polarizability and are associated with LUMO of lower energy
than hard acids.
Soft bases: electron-pair donors, in which the donor atoms have high
polarizability, low electronegativity, easily oxidizable and are associated with HOMO of
higher energy than hard bases.
5
Consequently, acids and bases can be categorized into three classes, namely hard,
soft and borderline (Table 1.2). The HSAB principle allows qualitative predictions of
reaction mechanisms and pathways and the relative stabilities of the products. However,
this principle does not give a precise definition of hardness or softness and does not allow
a quantitative scale to be established. More recently, Christe and Dixon have predicted
Lewis acid strength based on ab initio calculations of gas phase affinity for fluoride.
15

Out of 106 common isolable Lewis acids, they found that SbF
5
had the strongest fluoride
affinity. However, this computational method is limited to the study of hard Lewis base
whereas soft Lewis bases are very difficult to study.

6
Table 1.2 Classification of some common Lewis acids and bases
9

Hard Borderline Soft
Acids
H
+
, Li
+
, Na
+
, K
+
Fe
2+
, Co
2+
, Ni
2+
, Pd
2+
, Pt
2+

Cu
2+
, Zn
2+

Be
2+
, Mg
2+
, Ca
2+
, Sr
2+
B(Me)
3
, GaH
3

Cu
+
, Ag
+
, Au
+
, Hg
+
,
Hg
2+

Sc
3+
, La
3+
, Ce
4+
, UO
2
2+
R
3
C
+
, NO
+
, Bi
3+
BH
3
, Ga(Me)
3

Ti
4+
, Cr
3+
, Mn
2+
, Fe
3+
, Co
3+
SO
2
π Acceptors

(trinitrobenzene,
quinones,
tetracyanoethylene)
BF
3
, BCl
3
, Al
3+
, Al(Me)
3
, Ga
3+
Br
2
, Br
+
, I
2
, I
+
, ICN
CO
2
, RCO
+
, Si
4+

SO
3

HX (hydrogen-bond donor)
Bases
NH
3
, RNH
2
C
5
H
5
N, N
3
-
H
-

H
2
O, OH
-
, ROH, R
2
O NO
2
-
, SO
3
2-

C
2
H
4
, C
6
H
6
, CN
-
,
CO
CH
3
COO
-
, CO
3
2-
, NO
3
-
, SO
4
2-
Br
-

SCN
-
, R
2
S, RSH,
RS
-

F
-
, Cl
-
R
3
P, R
3
As
I
-

1.1.1 The Need for Green Lewis Acid Catalyst
It is widely accepted that the concept of ‘green chemistry’, also known as
sustainable chemistry has grown substantially in the last decade. In the United States, the
concept of green chemistry did not actually emerge until the passage of the Pollution
Prevention Act of 1990. The law guided the Environmental Protection Agency to
establish its Green Chemistry Program in 1991 in which pollution prevention strategy,
7
and source reduction models developed.
16
At that time, Paul T. Anastas defined the term
‘green chemistry’ for the first time. His concept is embodied in the 12 Principles of Green
Chemistry
17-20
which can be summarized as:
1. Waste prevention is better than remediation.
2. All material should be used efficiently.
3. Less hazardous/toxic chemicals.
4. Safer products by design.
5. Harmless solvents and auxiliaries.
6. Energy efficient by design.
7. Preferable recyclable raw materials.
8. Shorter syntheses (avoid derivatization).
9. Catalytic rather than stoichiometric reagents.
10. Design products for degradation.
11. Analytical methodologies for pollution prevention.
12. Naturally safer processes.
As the concept develops, it becomes obvious that catalysis is one of the major
tools for the development and implementation of green chemistry. Catalysis not only
improves reaction selectivity but also decreases or even removes the need for
downstream processing. As a result, the material and energy waste associated with
purification processes can be reduced. Therefore, catalysis is one of the major strategies
in developing green chemistry particularly when the solvent requirements for reaction
purification processes such as recrystallization, chromatography, etc., are often much
greater than the usage of solvent in the original reaction.
19

8
While a variety of Lewis acid catalyzed processes have been developed and many
have been used within the industry, there is a great need for greener alternatives for
conventional Lewis acids such as AlCl
3
and TiCl
4
. These conventional Lewis acid
catalyzed processes mainly focused on product yield, while the environmental impact of
inorganic waste and toxic by-products formed during the reactions were disregarded. For
example, many conventional Lewis acid catalyzed reactions requires stoichiometric or
excess amounts of Lewis acids and are not reusable. Quenching of the acid-base adduct
formed between the catalyst requires water which completely decomposes the Lewis acid
and form hazardous wastes. A prominent example of the above operational procedure is
the Friedel-Crafts acylation, a commonly applied reaction in the industry. Like many
other conventional Lewis acid catalyzed reactions, Friedel-Crafts acylation also requires
more than one equivalent of the Lewis acid catalyst, such as AlCl
3
or BF
3
, with the
common reason that reaction products are stronger bases than the reactants. The
traditional process using acetyl chloride in combination with 1.1 equivalents of AlCl
3
in
halogenated solvent, generates 4.5 kg of wastes including HCl and acetic acid, per kg of
product.
5,19
Due to the reasons mentioned above and the water sensitive nature of
conventional Lewis acids, it is a common practice to use greater than stoichiometric
amounts of the Lewis acids. As a result, the amount of byproducts and waste derived
from Lewis acids is large. Therefore, there is an urgent need for green Lewis acid
catalyst.
One approach is to develop molecular frameworks with active Lewis acidic sites;
such as zeolites or mesoporous silicas.
5,20-21
Another approach is to develop water
compatible Lewis acids. Indeed, lanthanide triflates, such as Sc(OTf)
3
, Yb(OTf)
3
, can be
9
prepared in water and are water compatible.
22
The use of water compatible Lewis acid
catalysts was pioneered by Kobayashi and coworkers.
23-25
These new types of Lewis acid
catalysts have the advantages of being water compatible and air stable, which allows for
easy execution of reaction procedures, and are often associated with the extra advantage
of high functional group tolerance.
26
The actual catalysis in actual media could be of
Brønsted acid origin, however. The characteristics of being water tolerant and
recoverable from water shows their significant potential as safe and environmentally
benign catalysts. These new types of Lewis acid catalysts have been widely applied to
various organic transformations, such as C,C or C,X (X=N, O, P, etc.) bond formation,
oxidations, reductions, rearrangements, protection, deprotection, and polymerizations,
etc.
25-26
Among these applications the rare earth metal triflates have played a dominant
role while the triflates of group IIIA metals (B, Al, Ga) are much less studied.
Recently, we have successfully applied a group IIIA metal triflate (Ga(OTf)
3
) into
various reactions. It has been found that Ga(OTf)
3
acts as nonhydrolyzable, air stable
Lewis acid catalyst for many organic synthetic transformations, such as Friedel-Crafts
acylation, alkylation and hydroxyalkylation, dehydration of oximes to the corresponding
nitriles, epoxyolefin cyclization, Beckman rearrangement, annulation, etc.
27
The activity
of Ga(OTf)
3
is found to be comparable and in most cases even superior than most well-
known rare earth metal triflates such as Yb(OTf)
3
, Y(OTf)
3
and Sc(OTf)
3
.
28
The
environmentally friendly characters of Ga(OTf)
3
of being water tolerant, easily recovered
and reused without loss of activity were further demonstrated in the synthesis of β-
hydroxy sulfoxides and the three-component Mannich reaction performed in sole water
by Jin et al
29
and Zou et al,
30
respectively. The versatility of Ga(OTf)
3
was further
10
confirmed by the synthesis of β–enamino ketones and pyrroles under solvent-free
conditions.
26

1.1.2 Trimethylsilyl Trifluoromethanesulfonate (TMSOTf) as a Strong Lewis Acid
Catalyst

Contrary to more traditional Lewis acids, the synthetic applications of
organosilicon compounds as Lewis acids have a relatively brief history. In the early
studies, organosilicon compounds were mainly used to develop selective protective
methods for various protic functional groups.
31
However, the tendency of the silicon atom
to expand its valence shell to five and six coordinate intermediates allows one to consider
many silylating agents as effective Lewis acids.
32
Indeed, silicon based Lewis acids
contrast sharply with conventional metal-centered activators. Organosilicon Lewis acids
are compatible with many silyl enol ethers, allyl organometallic reagents, and cuprates.
Unlike metal halides, organosilicon Lewis acids do not tend to undergo aggregation and
disproportionation or ligand exchange.
3

Most frequently used C-C bond forming organosilicon Lewis acids are
commercially available. However, they are very readily hydrolyzed by moisture, forming
free acid, which can significantly change the outcome of the reactions catalyzed by the
organosilicon Lewis acids. Thus they are occasionally freshly prepared before use. The
most important method for the preparation of silylperfluoroalkane sulfonates is the
protodesilylation of allyl- or aryl-substituded trialkylsilanes with perfluoroalkane sulfonic
acids. Alternatively, they can be prepared by reactions of trialkylsilyl chloride with the
corresponding acid or silver salt. Various trialkyliodosilanes can be prepared by reactions
11
of trialkylsilyl chloride and sodium iodide in acetonitrile or by reactions of trialkylsilanes
with alkyl iodide catalyzed by PdCl
2
(Scheme 1.2).
33

R
3
SiX
R
3
SiCl + AgX
NaI
-NaCl -AgX
R
3
SiY HX
Y = allyl, Ph, H, Alk
-HY
-AlkH
cat. PdCl
2
R
3
SiH + AlkI
R
3
SiCl
+
+

Scheme 1.2 Synthesis of silicon Lewis acids
32

Trimethylsilyl triflate (Me
3
SiOTf) is undoubtedly the most versatile and
representative organosilicon Lewis acid pioneered by Noyori in the early eighties.
34

Me
3
SiOTf is a hard Lewis acid that activate polar multiple bonds in aldehydes, ketones,
esters, imines as well as polar single bonds in acetals, orthoesters, ethers, aminals, or C-
Cl bonds in α-heterosubstituted chloroalkanes.
35
The purpose of Me
3
SiOTf is to activate
the electrophilic component serving as a Lewis base (e.g., imines) in the reaction of a C-
C bond forming reaction between electrophiles (E) and nucleophiles (Nu). In addition,
only a catalytic amount of the organosilicon Lewis acid is needed if Me
3
SiOTf and the
nucleophile (e.g., Me
3
SiCN) have the similar trialkylsilyl fragments. Therefore,
depending on the type of electrophile, two major pathways are possible (Scheme 1.3).
32

12
R
3
Si-Y=E X
-
Nu-SiR
3
R
3
Si-Y-E-Nu-SiR
3
X
-
R
3
Si-Y-E-Nu
R
3
SiX
Y=E
R
3
SiY
X
-
Nu-SiR
3
E-Nu-SiR
3
X
-
E-Nu
Y-E
E
+
+
R=Me
X=OTf

Scheme 1.3 General mechanistic pathways of organosilicon Lewis acid
32

For acetals and similar compounds, the first step involves the silylation of 1 with
TMSOTf to afford the oxonium ion A, which is in equilibrium with the carbocation B.
Nucleophilic substitution on A or addition to B give the ionic intermediate C. Elimination
of TMSOTf from C gives the final product 2 (Scheme 1.4).
35

R
2
OR
3
R
1 OR
3
+ TMSOTf
R
2
OR
3
R
1 OR
3
SiMe
3
R
2
R
1
O
R
3
CF
3
SO
3
1
Nu-TMS
R
2
Nu-TMS
R
1 OR
3
CF
3
SO
3
-TMSOTf
R
2
Nu
R
1 OR
3
A B
C 2

Scheme 1.4 General reaction mechanism of TMSOTf with acetal or acetal-like
compounds
32

On the other hand, when the substrates contain carbon-heteroatom double bonds
(e.g., carbonyl compounds, imines), Me
3
SiOTf will initially bind to the basic function of
3 and forms complex D.
5,35-36
The electrophilic carbon center of the activated complex
13
then undergoes nucleophilic attack by the nucleophile (e.g., silyl enol ether, silyl ketene
acetal, Me
3
SiCN) to give intermediates E. The intermediate E is then transformed into
the final product 4 rapidly (Scheme 1.5).
5,35
It is important to note that nucleophilic
substitution at the silicon atom always proceeds through the five-coordinate intermediate
5 by the associative mechanism independent of the mechanistic pathway (Scheme 1.6).
32

However, the equilibrium concentrations of both five-coordinate intermediate 5 and
cationic complex 6 can be very low in the reaction mixture, especially when TMSOTf is
used as the organosilicon Lewis acid. Furthermore, the possibility of the reaction to occur
is highly dependent on several factors such as the nature of the electrophile, the reactivity
of the nucleophile and the strength of the silicon-heteroatom bond.
5

R
1
O
R
2
R
1
O
R
2
SiMe
3
CF
3
SO
3
Nu-TMS
R
1
O
Nu
R
2
SiMe
3
SiMe
3
CF
3
SO
3
-TMSOTf
R
1
O
Nu
R
2
SiMe
3
+ TMSOTf
3 D
E 4

Scheme 1.5 General mechanism of TMSOTf catalyzed reactions of carbonyl
compounds
32

14
Nu +
Si X Nu Si X Nu Si X
-
+
5 6
X = OTf

Scheme 1.6 Principles of catalytic action of TMSOTf
32

In the case of substrates possessing imine functionality 7, which are less
electrophilic than carbonyl compounds (Scheme 1.7),
32
the introduction of an electron-
withdrawing substituent (EWG, 8a,b) or oxygen atoms at the nitrogen atom (nitrones 9,
nitronates 10) is expected to enhance the electrophilicity of the C=N bond. As mentioned
before, the reactions of imines with Me
3
SiOTf would be expected to produce N-
silyliminium cations 11 (Scheme 1.8)
32
similar to siloxonium ion D (Scheme 1.5). In
some cases, electron-withdrawing substituents such as, sulfono, sulfoxy, phosphinoyl,
ester or trifluoromethyl are used in combination with Lewis acid to doubly activate the
imines for the reaction to proceed.
R
1
N
R
2
R
3
R
1
N
R
2
EWG
EWG
N
R
2
R
3
R
1
N
R
2
R
3
O
R
1
N
R
2
OR
3
O
7 8a 9 10 8b

Scheme 1.7 Activation of C=N bond
5,32

R
1
N
R
2
R
3
R
1
N
R
2
R
3
(H
3
C)
3
Si
TMSOTf
OTf
11

Scheme 1.8 Reactions of imines with TMSOTf
5,32

15
1.1.3 Significance of Organofluorine compounds
Fluorine plays important roles in many different fields such as agrochemical,
medicinal and pharmaceutical research and material science.
37
It is well known that the
incorporation of fluorine atoms into biologically active molecules often results in
significant changes in their metabolic stability, lipophilicity, and bioavailability.
38-40

Indeed, research has shown the important effects of fluorine substitution on the inter- and
intramolecular forces, which affect ligand binding. As a result, fluorine substitution has a
profound effect on drug disposition, drug clearance, and the extent of drug metabolism
because of its small size, high electronegativity and the ability to form strong C-F
bonds.
41-42
One classic example is the longest established anti-cancer drug, 5-fluorouracil,
prepared in 1957, which still has important clinical applications even 50 years after its
original discovery.
43-44
To date, up to 35% of agrochemicals and 20% of pharmaceuticals
on the market contain fluorine, including 4 in the top 10 best-selling drugs.
45
Other well
known fluorinated drugs containing one F atom or a CF
3
group are shown in Figure 1.1.
Consequently, there have been intensive studies on fluorinated compounds, including
total synthesis, methodology studies and reaction mechanism studies. Also, the scarcity
of natural organofluorine compounds makes the investigation of fluorine chemistry even
more important. Nowadays, most of the fluorinated products utilized were obtained from
synthetic methods. From another perspective, there have been special synthetic
challenges present in synthesizing fluorinated compounds, and also unique
structure/reactivity relationships observed for fluorine-containing compounds.
16
HN
N
H
O
O
F
5-Fluorouracil
N N
F
O
COOH
HN
Ciprofloxacine
N
N
CF
3
H
3
C
H
3
CO
2
S
Celecoxib
F
3
C
O
H
N
Fluoxetin

Figure 1.1 Common fluorinated drugs

One category of fluorinated compounds that is noteworthy is those with chirality
and used as pharmaceutical products. The regulation of chiral compounds in the market is
forcing the development of asymmetric synthesis of organofluorine compounds,
producing enantiopure fluorinated molecules. There have been examples of asymmetric
nucleophilic fluorinations but these are limited to the ring opening of meso-epoxides by
Jacobsen’s catalyst in up to 72% ee.
46
Fluorinating agents developed in the early stages
required several synthetic steps and the handling of hazardous molecular fluorine for N-F
bond formation. A breakthrough came from the discovery of naturally occurring
Cinchona Alkaloids, i.e. N-fluoroammonium salts of Cinchona Alkaloids (Figure 1.2)
prepared in a one-step transfer fluorination on cinchona alkaloids or N-
fluorobenzenesulfonimide (NFSI). The catalytic electrophilic fluorination using
Cinchona alkaloid has been applied to enantioselectively synthesize fluorooxindole
17
BMS-204352, a potent opener of maxi-K channel,
47
and an analog of a specific inhibitor
of type I DNA topoisomerase (Figure 1.3).
48

N
N
R
2
R
1
O
F
X
-
N
N
R
2
OR
1
F
X
-

Figure 1.2 Chiral electrophilic fluorinating agents

H
N
O
F
Cl OMe
F
3
C
N
N
O
O
O F
BMS-204352
96%, 88% ee (>99% after recrystallization)
Fluorocamptothecin
87%, 88%ee

Figure 1.3 Fluorinated drugs prepared by enantioselective electrophilic
fluorination

Instead of synthesizing fluorinated reagents before the actual fluorination steps,
organocatalysis emerges as an attractive alternative method that is growing fast in
asymmetric synthesis leading to high enantioselectivities. Kim and Park first reported an
enantioselective phase transfer catalyzed electrophilic fluorination of ketoesters mediated
by a chiral cinchonidine derived quaternary ammouium salt with 70% ee. In 2005,
imidazolidinones and proline derivatives were used as organocatalysts for
enantioselective fluorination of aldehydes and ketones. Up to 99% ee was achieved for
18
aldehydes and only 36% ee for ketones.
46
Very recently, our group published an
organocatalytic fluorination method which demonstrated an efficient stereoselective
Michael addition to chalcones. In Chapter 7, a similar method will be utilized for the
conjugate addition of α–fluoro-α nitro-phenyl sulfonyl methane to α –nitroolefins.
On the other hand, there has also been an increase in demand of α-fluorinated
ethers and thioethers in medicinal chemistry.
37
The successful use of fluorinated ethers
and thioethers in the field of modern agrochemistry is already established by the
introduction of various commercial products such as insecticide Indoxacarb,
49
fungicide
Tetraconazole,
50
pesticide Triflumuron,
51
and plant growth regulator Flurprimidol
52

(Figure 1.4). However, few examples of trifluoromethyl ethers exist in the field of
medicinal chemistry.
53-55
α-fluorinated ethers can be used as volatile, non-toxic, non-
explosive and fast-acting anaesthetics and anti-inflammatory agents, cardiovascular drugs
(e.g. Celikalim)
56
, respiratory drugs (e.g. Roflumilast)
57
, psychopharmacologic drugs,
neurological drugs (e.g. Riluzole)
58
, gastrointestinal drugs and anti-infective therapeutics
(Figure 1.5).

19
O
N
N
O
N
COOCH
3
OCF
3
COOCH
3 Cl
Indoxacarb
Cl
Cl
OCF
2
CHF
2
N
N
N
Tetraconazole
Cl
H
N
O
H
N
O
OCF
3
Triflumuron
F
3
CO
OH
N
N
Flurprimidol

Figure 1.4 Fluorinated ethers as agrochemicals

N
O
O
F
3
CO
HO
Celikalim
F
2
HCO
O
O
N
H
N
Cl
Cl
Roflumilast
S
N
NH
2
F
3
CO
Riluzole

Figure 1.5 Fluorinated ethers as pharmaceuticals

20
1.2 Chapter 1: Aim and Scope of the Present Work
As mentioned above, organofluorine compounds are of great importance due to
their wide applications in various fields especially in medicinal chemistry. Therefore, one
of our goals is to develop new methodologies for the synthesis of potential biologically
active fluorinated analogs using a wide variety of readily available fluorine-containing
building blocks. Other route such as asymmetric fluorination was also explored. While
the importance of fluorinated ethers is well recognized and has been applied to
pharmaceutical chemistry, few methods are available for the syntheses of fluorinated
ethers.
37
In addition, the syntheses of these compounds require special reagents and
equipment. Thus, another goal was to develop a mild and efficient method for the
syntheses of fluorinated ethers.
As legislation on the release of waste and toxic emissions in the chemical industry
tightens, the demand for environmentally friendly methods can only increase. Thus,
another area that we were interested in is the development of “green”, simple and
practical methods using environmentally friendly Lewis acid catalyst, Ga(OTf)
3,
to
replace conventional Lewis acid catalyzed reactions. Green Lewis acid catalysts are
inexpensive, easily recoverable and reusable. Simple operation procedure, water and air
compatibility and low toxicity are the other attributes. In addition to the well studied
green Lewis acid catalysts Yb(OTf)
3
and Sc(OTf)
3
,
25
it has also been found that Ga(OTf)
3

can be used as a catalyst for different organic transformations.
26,28,30,59-70
Ga(OTf)
3
is air
and water tolerant, stable up to 280 °C, can be used in catalytic amounts and is easily
recovered thus emerging as a reusable, safe and environmentally benign catalyst.
71

21
Metal-free organocatalysis
72
is another area that we have focused on. The main
advantage of organocatalysis is that there are no metal-based catalysts involved, thus
making further contribution to green chemistry which is particularly valuable for
designing suitable drugs devoid of any metal content. Since the late 1970s, a series of
synthetic organic transformations have been reported using TMSOTf as a homogeneous
Lewis acid.
5
We have therefore explored the catalytic potential of TMSOTf as a good
metal free Lewis acid catalyst for various organic transformations.

22
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25
53. Manteau, B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2010, 131,
140.

54. Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827.

55. Jeschke, P.; Baston, E.; Leroux, F. R. Mini-Rev. Med. Chem. 2007, 7, 1027.

56. Quagliato, D. A.; Humber, L. G.; Joslyn, B. L. S., R. M.; Browne, E. N. C.; Shaw,
C.; Van Engen, D. Bioorg. Med. Chem. Lett. 1991, 1, 39.

57. Reid, P. Current Opinion in Investigational Drugs 2002, 1165.

58. Jimonet, P.; Audiau, F.; Barreau, M.; Blanchard, J.-C.; Boireau, A.; Bour, Y.;
Coleno, M.-A.; Doble, A.; Doerflinger, G.; Do Huu, C.; Donat, M.-H.; Duchesne,
J. M.; Ganil, P.; Gueremy, C.; Honore, E.; Just, B.; Kerphirique, R.; Gontier, S.;
Hubert, P.; Laduron, P. M.; Blevec, J. L.; Meunier, M.; Stutzmann, J.-M.;
Mignani, S. J. Med. Chem. 1999, 42.

59. O'Hagan, D. Chem. Soc. Rev. 2008, 37, 308.

60. Smar, B. E. J. Fluorine Chem. 2001, 109, 3.

61. Nicolas, F.; Morel, B.; Belhomme, C.; Simon, C.; Salanne, M.; Lantelme, F.;
Groult, H. J. Fluorine Chem. 2007, 128, 285.

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65. Molina, M. J.; Rowland, F. S. Nature 1974, 810, 249.

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26
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1987, 52, 4314.

27
2 Chapter 2: Gallium(III) Triflate Catalyzed Direct
Reductive Amination of Aldehydes

2.1 Chapter 2: Introduction
Amines and their derivatives act as important synthetic precursors in organic
chemistry. They are highly versatile building blocks for various organic target molecules
and are essential precursors to a variety of biologically active compounds, such as
pharmaceuticals
1
and agrochemicals.
2
Due to their importance, numerous methods have
been developed for the preparation of amines. Reductive amination of aldehydes and
ketones, in which a mixture of an aldehyde or ketone and an amine is treated with a
reductant in a one-pot fashion, is also one of the most useful methods for the preparation
of secondary or tertiary amines and related functional compounds in biological and
chemical systems.
3-6
The major advantage of this reaction is that there is no need to
isolate intermediate imines, in particular, in cases imines are unstable. The choice of the
reducing agent is very crucial for the success of the reaction, since the selective reduction
of imines (or iminium ions) by the reducing agent over aldehydes or ketones is required
under the reaction conditions.
7, 8

The two most commonly used direct reductive amination methods differ in the
nature of the reducing agent. The first method is catalytic hydrogenation with platinum,
palladium, or nickel catalysts. This is an economical and effective reductive amination
method, particularly in large scale reactions. However, hydrogenation has limited use
with compounds containing other reducible functions such as carbon–carbon multiple
28
bonds, nitro and cyano groups. Inhibition of the catalytic activity of the catalyst by sulfur
compounds has also been observed.
The second method utilizes hydride based reducing agents.
8
Among the hydride
based reducing agents,
5-9
different borohydrides are frequently used to carry out this
transformation, mainly sodium cyanoborohydride (NaBH
3
CN) and sodium
triacetoxyborohydride {NaBH(OAc)
3
}
8, 10, 11
However, most of these reagents have one
drawback or another. For example, cyanoborohydride and tin hydride are highly toxic
and generate toxic byproducts such as HCN, NaCN, or organotin compounds.
12
Upon
workup, contamination of the product with the toxic compounds has been observed in
many cases. Other hydrides such as sodium triacetoxyborohydride also involve the use of
corrosive acetic acid.
13
The processes based on such reducing agents are not
environmentally friendly and do not conform with the principles of green chemistry and
sustainable development. Hence, the developments of improved methods involving easily
tunable and environmentally friendly protocols are still in high demand.
2

Reductive amination of aldehydes using various reducing agents were recently
reported.
14-17
There are, however, only few reports on the direct catalytic reductive
amination of carbonyl compounds using organosilane as a reducing reagent. Hydrosilanes
such as triethylsilane in the presence of acid catalysts
18
and molecular hydrogen in the
presence of water-soluble transition metal catalysts
19
are mild and useful reagent systems
for reduction. Apodaca and coworkers
20
showed that the direct reductive amination with
carbonyl compounds using phenylsilane (PhSiH
3
) was achieved in the presence of
catalytic amount of dibutyltin dichloride. Titanium catalyzed reduction of imines
previously prepared from the reaction of amines with aromatic and nonaromatic ketones
29
with PhSiH
3
and polymethylhydrosiloxane (PMHS) was also reported by Buchwald and
coworkers.
21
Recently, reductive amination of aldehydes and ketones using
PMHS/trifluoroacetic acid system has been reported.
22
Our recent studies using gallium
(III) trifluoromethanesulfonate {Ga(OTf)
3
, gallium triflate} showed that it acts as an
effective but mild and water tolerant Lewis acid catalyst for many organic synthetic
transformations such as Friedel–Crafts alkylations, dehydration of oximes to the
corresponding nitriles, Beckman rearrangement.
23-30
It has been found that gallium triflate
offers the optimum acidity required for ketonic Strecker reaction
31
and the synthesis of
various heterocycles such as dihydrobenzimidazolines, benzothiazolines,
benzoxazinones
32
etc. Intrigued by these results, we decided to carry out direct
hydroamination in a three component fashion using aldehydes and amines in the presence
of hydrosilanes using Ga(OTf)
3
as catalyst.

2.2 Chapter 2: Results and Discussion
From our preliminary study, we found that gallium triflate can efficiently catalyze
the direct reductive amination of aldehydes under mild conditions (Scheme 2.1). As
shown in the previous cases,
23-31
gallium triflate can be easily recovered from the reaction
mixture and reused, showing its significant potential as a safe and environmentally
benign catalyst. The procedure offers broad application and the synthesis of diverse
higher secondary amines with a high degree of functional group tolerance.
30
CHO
N
H
R
NH
2
R
1
R
+
R
1
Organosilane
Ga(OTf)
3
(5 mol%)
CH
2
Cl
2
, 100
0
C
2.5-12 h
1 2 3

Scheme 2.1 Gallium triflate catalyzed reductive amination of aldehydes

The direct reductive amination of 4-methoxybenzaldehyde with 4-chloroaniline in
the presence of 5 mol% of Ga(OTf)
3
was selected as a model reaction and was examined
under the influence of several organosilanes reductants (Table 2.1). Reductive amination
was found to be feasible with triethylsilane, phenylsilane, and polymethylhydrosiloxane
(PMHS). However, sterically hindered organosilanes, such as, triisopropylsilane (entries
2, 4 and 5) were ineffective. The steric factors associated with different organosilane
reductants seem to be important in determining the fate of the reaction. Of these three
effective reductants, triethylsilane was the most suitable (entries 2 and 5) and PMHS
produced an insoluble precipitate which required tedious purification procedure (entry 7).
Reactions performed with substoichiometric amount of phenylsilane or triethylsilane
suggest that excess silane was required as the hydride source for 100% conversion
(entries 1, 2, 5, and 6). No reductive amination was observed with triethylsilane in the
absence of Ga(OTf)
3
(entry 3a), demonstrating the essential role of Ga(OTf)
3
as the
catalyst.
15

31
Table 2.1 Screening of organosilane reductants for gallium triflate catalyzed reductive
amination of aldehydes
Entry Organosilane (equiv.) Yield (%)
a
1
2
3
b
4
5
7
Et
3
SiH (1.1)
Et
3
SiH (3.0)
Et
3
SiH (3.0)
PhSiH
3
(1.1)
PMHS (2.8)
((CH
3
)
2
CH)
3
SiH (3.0)
Conversion (%)
48
100
0
-
0 -
-
98
6
PhSiH
3
(3.0)
b
Reaction was performed in the absence of Ga(oTf)
3
100 97
55 -
- 25
CHO NH
2
Cl OMe
+
MeO
N
H
Cl
1b 2c 3e
Organosilane
Ga(OTf)
3
(5 mol%)
CH
2
Cl
2
, 100
0
C, 12h
a
Isolated yield.

From the screening of different organosilanes in varying amounts and studying
their efficiency as effective reducing agents (Table 2.1), it has been found that
triethylsilane and phenylsilane are the most efficient reducing agents under the reaction
conditions when they are used in excess (3 M equivalents). Use of dichloromethane
minimizes solvent interaction with the catalyst resulting in enhanced catalytic activity of
the catalyst towards aldehydes and the resultant imines providing suitable environment
for further reduction step.
Additionally, it is worth noticing that no reduction of aldehyde 1 to alcohol or the
corresponding silyl ether occurred during the reaction. It shows that in the presence of
32
Table 2.2 Ga(OTf)
3
catalyzed reductive amination of aldehydes with triethylsilane
Aldehydes (1) Amines (2) Product (3) Time (h) Yield (%)
a
Entry
H
2
N
1
CHO
Cl
Cl
N
H
H
2
N
2
CHO
Cl
Cl
N
H
CH
3
CH
3
H
2
N
3
CHO
Cl
Cl
N
H
Cl
Cl
3
H
2
N
4
CHO
MeO
MeO
N
H
88
78
97
87
H
2
N
5
CHO
MeO
MeO
N
H
Cl
Cl
98
CHO
MeO
CH
3
H
2
N
6
MeO
N
H
CH
3
94
H
2
N
8
CHO
Et
Et
N
H
89
CHO
H
2
N
Cl
N
H
Cl
7
OCH
3
H
3
CO
OCH
3
H
3
CO 95 2.5
4.5
3
2.5
2.5
3
3
H
2
N
9
CHO
Et
Et
N
H
Cl
Cl
95 3.5
1a 2a
2b
2c
1b
1c
1d
3a
3b
3c
3d
3e
3f
3g
3h
3i

33
Table 2.2 continued
H
2
N
12
CHO
O
2
N
O
2
N
N
H
Cl
Cl
95
H
2
N
13
CHO
O
2
N
O
2
N
N
H
98
OCH
3
OCH
3
H
2
N
14
CHO
NC
NC
N
H
91
Cl
Cl
H
2
N
15
CHO
N
H
Cl
Cl
CH
3
87
CHO
F H
2
N
Cl
F
N
H
Cl
16
CHO
H
2
N
Cl
N
H
Cl
17
F
F
73
68
2.5
2.5
5
4.5
4.5
3
CHO
H
2
N
10
N
H
93
CHO
H
2
N
11
N
H
Cl
Cl
97
4
4.5
H
3
C
H
3
C
CH
3
O
H
H
2
N
OCH
3
H
3
C
H
3
C
H
3
C H
H
N
H
OCH
3
CHO
Cl H
2
N
NO
2
Cl
N
H
NO
2
18
19
12 94
2.5 85
Aldehydes (1) Amines (2) Product (3) Time (h) Yield (%)
a
Entry
1e
1f
1g
1h
1i
1j
1k
2d
2e
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s

34
Ga(OTf)
3
, chemoselective reduction of aldimine 4 is preferred to the reduction of
aldehydes 1 under the reaction conditions. A recent study by Laali et al.
44
showed that
formation of the corresponding benzyl ether was predominant during the Lewis acid
catalyzed hydrosilylation of aldehydes and ketones using various metal triflates including
Ga(OTf)
3
. Therefore, we also examined the chemoselective reductive amination of
functionalized benzaldehydes bearing other reducible functional groups employing the
same methodology. As indicated in (Table 2.2), aromatic aldehydes having chloro,
fluoro, methoxy, nitro and cyano groups smoothly underwent reductive amination to give
the corresponding N-phenyl amines in good yields without affecting other functional
groups (entries 1–3, 12–14, 16 and 17). Similarly aliphatic aldehydes such as
pivalaldehyde underwent reductive amination successfully with 4-chloroaniline to give
the corresponding amine in high yield (entry 18).
Aromatic amines containing electron withdrawing substituents, such as nitro and
chloroanilines, are poor nucleophiles as well as weak bases (e.g., pKa 3.98 for 4-
chloroaniline, 1.02 for 4-nitroaniline).
8
This slows down the initial nucleophilic attack on
the carbonyl carbon by the amine and leads to slower overall reaction rates (Scheme 2.2).
In addition, the carbonyl group now competes effectively with the less basic intermediate
imine for protonation (or complexation with Lewis acid) and the subsequent hydride
reduction step.
45
This may lead to a significant carbonyl reduction, consumption of both
the carbonyl compound and the reducing agent, and low yields of the reductive amination
products. Hence, NaBH
3
CN, the most widely used hydride reagent for the reductive
amination of aldehydes and ketones, was found to be a sluggish and inefficient reagent
for this purpose.
8
However, Ga(OTf)
3
catalyzes the reaction of both 4-nitro and 4-
35
chloroaniline with aromatic aldehydes and the subsequent triethylsilane reduction to the
corresponding secondary amines very effectively (entries 9, 19).
3

Based on the efficient reductive amination protocol for aldehydes catalyzed by
Ga(OTf)
3
, we decided to extend this methodology to ketones also. However, it was found
that the reactions were not feasible and clean under similar conditions. Several
modifications of the reaction conditions (changing temperature, reaction time, catalyst
loading etc.) did not result in any significant improvement.
N
H
H
R
1
H
O
H
R
1
N
O
R
2
H
H
Ga(OTf)
3
H
OH
N
R
1
R
2
H
H R
1
N
R
2
H R
1
N
R
2
+
Ga(OTf)
3
H Si(Et)
3
R
2
H
H
N
R
1
R
2
Si(Et)
3
H
H
N
R
1
R
2
H
-H
2
O
H
2
O
-Et
3
SiOH
(Et
3
Si)
2
O
1 2
4 3
Ga(OTf)
3

Scheme 2.2 Proposed mechanism of the Ga(OTf)
3
catalyzed direct reductive amination

The suggested mechanism, involved in this reaction is schematically shown in
(Scheme 2.2). The first step involves the formation of the aldimine intermediate 4 from
the Ga(OTf)
3
catalyzed condensation reaction between aldehyde and amine. Aldimine 4
activated by coordination with the Lewis acid Ga(OTf)
3
undergoes subsequent silane
addition followed by hydrolysis to yield the secondary amines 3 as the reduction product.
Conversion and yield of the secondary amines 3 depend on the amounts of organosilane
used. Absence of organosilane stops the reaction at the aldimine stage manifesting its role
36
as the hydride source under gallium triflate catalysis. When reduction has been attempted
in the absence of Ga(OTf)
3
, no reduction product has been observed. When the imine
prepared separately was subjected to reduction conditions in the absence of Ga(OTf)
3
, no
change was observed, further emphasizing the catalytic role of Ga(OTf)
3
.

2.3 Chapter 2: Conclusion
In summary, we have developed a simple direct reductive amination procedure for
aldehydes, which employs triethylsilane as an effective reductant and Ga(OTf)
3
as a
catalyst. These reducing systems are superior due to their broad application in the
synthesis of diverse higher secondary amines with a high degree of functional group
tolerance. The simple experimental protocol, involving easy product isolation procedures
without chromatographic separations, excellent yields combined with effective
regeneration of the catalyst, is expected to contribute significantly towards efficient green
synthesis of highly functionalized amino compounds.

2.4 Chapter 2: Experimental
2.4.1 General
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. Ga(OTf)
3
was prepared by following a reported procedure.
25
The products were
identified by
1
H,
13
C,
19
F NMR and GC–MS spectral analysis.
1
H,
13
C, and
19
F NMR
spectra were recorded on 400 MHz Varian NMR spectrometer using CDCl
3
as solvent.
1
H and
13
C NMR chemical shifts were determined relative to tetramethylsilane (TMS) at
37
δ 0.0 ppm or to residual solvent peak at δ 7.26 ppm for CDCl
3
.
13
C NMR shifts were
determined relative to TMS at δ 0.00 ppm or to the residual solvent peak (at δ 77.16 ppm
for CDCl
3
).
19
F NMR chemical shifts were determined relative to internal standard CFCl
3

at δ 0.00 ppm. Mass spectra were recorded on Agilent HP 5973 Mass Spectrometer in the
EI mode.

2.4.2 General Procedure for Ga(OTf)
3
-Catalyzed Reductive Amination of
Aldehydes

Aldehyde (2.04 mmol) and amine (2 mmol) dissolved in 4 mL of CH
2
Cl
2
was
added to Ga(OTf)
3
(52 mg, 5 mol%) in a pressure tube. Organosilane in excess (6 mmol)
was then added to the reaction mixture and the pressure tube was closed. The mixture
was stirred at 100
0
C until the completion of the reaction (monitored at different time
intervals by TLC and NMR). The mixture was then filtered and the residue was washed
with CH
2
Cl
2
(2 × 5 mL). The combined filtrate was concentrated under reduced pressure
and the product obtained was further purified by trituration of the residue with excess
hexane followed by evaporation of hexane.
2.4.3 Spectral Data
The
1
H and
13
C spectra of the products 3a,
33
3b,
34
3c,
35
3d,
36
3e,
37
3f,
38
3j,
39
3m
40

and 3o,
41
3r
42, 43
and 3s
22
were consistent with those reported.

38
4-Chloro-N-(2,5-Dimethoxybenzyl)Aniline (3g)
N
H
Cl
OCH
3
H
3
CO

1
H NMR (400 MHz, CDCl
3
): δ 7.10–7.15 (m, 2H), 6.89–6.76 (m, 3H), 6.68–6.63 (m,
2H), 5.46 (bs, 1H), 4.30 (s, 2H), 3.82 (s, 3H), 3.72 (s, 3H).
13
C NMR (100.63 MHz,
CDCl
3
): δ 153.67, 151.58, 146.90, 129.07, 128.15, 122.01, 115.35, 114.26, 112.25,
111.24, 55.93, 55.79, 43.70. MS (m/z): 277 (M
+
), 151 (100, M
+
-NHC
6
H
4
Cl).
N-(4-Ethylbenzyl)Aniline (3h)
Et
N
H
Cl

1
H NMR (400 MHz, CDCl
3
): δ 7.26–7.06 (m, 6H), 6.81–6.70 (m, 1H), 6.65 (dt, J = 9.11,
8.88, 3.99 Hz, 2H), 5.47 (bs, 1H), 4.22 (s, 2H), 2.58 (q, J = 7.59 Hz, 2H), 1.19 (t, J = 7.61
Hz, 3H).
13
C NMR (100.63 MHz, CDCl
3
): δ 145.98, 143.63, 134.99, 129.31, 128.13,
128.05, 119.29, 114.44, 49.32, 28.53, 15.62. MS (m/z): 211 (M
+
), 119 (100, M
+
-
CH
3
CH
2
C
6
H
4
CH
2
).
4-Chloro-N-(4-Ethylbenzyl)Aniline (3i)
Et
N
H
Cl

1
H NMR (400 MHz, CDCl
3
): δ 7.29–7.24 (m, 2H), 7.13–7.10 (m, 4H), 7.08–7.03 (m,
2H), 4.38 (s, 2H), 2.58 (q, J = 7.61 Hz, 2H), 1.17 (t, J = 7.61 Hz, 3H).
13
C NMR (100.63
39
MHz, CDCl
3
): δ = 146.20, 134.40, 133.79, 130.41, 130.07, 128.63, 126.85, 123.63,
55.91, 28.61, 15.33. MS (m/z): 245 (M
+
), 119 (100, M
+
-CH
3
CH
2
C
6
H
4
CH
2
).
4-Chloro-N-(Naphthalen-2-ylmethyl)Aniline (3k)
N
H
Cl

1
H NMR (400 MHz, CDCl
3
): δ 7.82–7.72 (m, 4H), 7.48–7.41 (m, 2H), 7.40–7.36 (m,
1H), 7.16–7.04 (m, 2H), 6.69–6.58 (m, 2H), 5.60 (bs, 1H), 4.42 (s, 2H).
13
C NMR
(100.63 MHz, CDCl
3
): δ 144.05, 134.54, 133.42, 132.99, 129.37, 128.66, 127.92, 127.80,
126.88, 126.45, 126.20, 125.86, 124.74, 116.01, 50.13. MS (m/z): 267 (M
+
), 141
(100, M
+
-NHC
6
H
4
Cl).
4-Chloro-N-(4-Nitrobenzyl)Aniline (3l)
O
2
N
N
H
Cl

1
H NMR (400 MHz, CDCl
3
): δ = 8.15–8.10 (m, 2H), 7.54–7.41 (m, 2H), 7.15–7.02 (m,
2H), 6.60–6.46 (m, 2H), 5.03 (bs, 1H), 4.44 (s, 2H).
13
C NMR (100.63 MHz, CDCl
3
): δ =
147.19, 146.27, 144.90, 129.25, 127.97, 123.89, 123.55, 114.77, 48.09. MS (m/z): 262
(100, M
+
).

40
4-{(4-Chlorophenylamino)Methyl}Benzonitrile (3n)
NC
N
H
Cl

1
H NMR (400 MHz, CDCl
3
): δ 7.57 (d, J = 8.28 Hz, 2H), 7.43 (d, J = 8.04 Hz, 2H), 7.12–
7.06 (m, 2H), 6.58–6.52 (m, 2H), 5.45 (bs, 1H), 4.40 (s, 2H).
13
C NMR (100.63 MHz,
CDCl
3
): δ 144.40, 143.69, 132.44, 129.23, 128.06, 127.17, 118.77, 115.12, 111.11, 48.55.
MS (m/z): 242 (100, M
+
).
4-Chloro-N-(2-Methylbenzyl)Aniline (3o)
N
H
Cl
CH
3

1
H NMR (400 MHz, CDCl
3
): δ 7.23 (d, J = 7.34 Hz, 1H), 7.19–7.09 (m, 3H), 7.08–7.03
(m, 2H), 6.48–6.43 (m, 2H), 4.14 (s, 2H), 4.10 (bs, 1H), 2.29 (s, 3H).
13
C NMR (100.63
MHz, CDCl
3
): δ 146.38, 136.29, 136.27, 130.50, 129.09, 128.10, 127.60, 126.21, 122.24,
114.04, 46.55, 18.92. MS (m/z): 231 (M
+
), 105 (100, M
+
-CH
3
, -C
6
H
5
Cl).
4-Chloro-N-(3-Fluorobenzyl)Aniline (3q)
N
H
Cl
F

1
H NMR (400 MHz, CDCl
3
): δ 7.31–7.24 (m, 1H), 7.11–7.08 (m, 3H), 7.05–7.03 (d, J =
9.78 Hz 1H), 6.97–6.91 (m, 1H), 6.49–6.54 (m, 2H), 4.30 (s, 2H), 4.25 (bs, 1H).
13
C
NMR (100.63 MHz, CDCl
3
): δ 161.63 (d, J = 246.09 Hz), 146.17, 141.69 (d, J = 6.73
41
Hz), 130.20 (d, J = 8.23 Hz), 129.12, 122.71 (d, J = 2.24 Hz), 122.49, 114.27 (d, J =
11.97 Hz), 114.07 (d, J = 8.98 Hz), 113.99, 47.83 (d, J = 2.24 Hz).
19
F NMR (376.78
MHz, CDCl
3
): δ ppm - 113.28 (dd, J = 9.16, 6.10 Hz, 1F). MS (m/z): 235 (M
+
), 109 (100,
M
+
-NHC
6
H
4
Cl).

42
2.5 Chapter 2: Representative Spectra
Figure 2.1
1
H NMR Spectrum of 3l

43
Figure 2.2
13
C NMR Spectrum of 3l

ppm (t1)
0 50 100 150
O
2
N
N
H
Cl
44
Figure 2.3
1
H NMR Spectrum of 3o

45
Figure 2.4
13
C NMR Spectrum of 3o

ppm (t1)
0 50 100 150
N
H
Cl
CH
3
46
2.6 Chapter 2: References
1. Samuelsson, G. Drugs of natural origin; Swedish Pharmaceutical: Stockholm,
1992.

2. Tajbakhsh, M.; Lakouraj, M. M.; Mahalli, M. S. Synth. Commun. 2008, 38, 1976.
3. Alinezhad, H.; Tajbakhsh, M.; Zamani, R. Synlett 2006, 3, 431.
4. Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1.
5. Hutchins, R. O.; Natale, N. R. Org Prep Proc Int 1979, 11, 204.
6. Lane, C. F. Synthesis 1975, 3, 135.
7. Kato, H.; Shibata, I.; Yasaka, Y.; Tsunoi, S.; Yasuda, M.; Baba, A. Chem.
Commun 2006, 40, 4189.

8. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D.
J. Org. Chem. 1996, 61.

9. Heydari, A.; Khaksar, S.; Akbari, J.; Esfandyari, M.; Pourayoubi, M.; Tajbakhsh,
M. Tetrahedron Lett. 2007, 48, 1135.

10. Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett. 1990, 31,
5595.

11. Kim, H. O.; Carrol, B.; Lee, m. S. Synth. Commun. 1997, 27, 2505.
12. Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in organic synthesis; Butterworths:
London, 1987.

13. Nagaiah, K.; Kumar, V. N.; Rao, R. S.; Reddy, B. V. S.; Narsaiah, A. V.; Yadav,
J. S. Synth. Commun. 2006, 36, 3345.

14. Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M. O., A. Tetrahedron Lett. 2002,
43, 3105.

15. Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org. Lett.
2006, 8, 741.

16. Mizuta, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005, 70, 2195.
17. Menche, D.; Arikan, F. Synlett 2006, 841.
47
18. Chen, B.-C.; Sundeen, J. E.; Guo, P.; Bednarz, M. S.; Zhao, R. Tetrahedron Lett.
2001, 42, 1245.

19. Robichaud, A.; Ajjou, A. N. Tetrahedron Lett. 2006, 47, 3633.
20. Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745.
21. Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 713.
22. Patel, J. P.; Li, A.; Don, H.; Korlipara, V. L.; Mulvihill, M. J. Tetrahedron Lett.
2009, 50, 5975.

23. Prakash, G. K. S.; Yan, P.; Torok, B.; Bucsi, I.; Tanaka, M.; Olah, G. A. Catal.
Lett. 2003, 85, 1.

24. Prakash, G. K. S.; Yan, P.; Torok, B.; Olah, G. A. Synlett 2003, 4, 527.
25. Prakash, G. K. S.; Yan, P.; Torok, B.; Olah, G. A. Catal. Lett. 2003, 87, 109.
26. Yan, P.; Batamack, P.; Prakash, G. K. S.; Olah, G. A. Catal. Lett. 2005, 101, 141.
27. Yan, P.; Batamack, P.; Prakash, G. K. S.; Olah, G. A. Catal. Lett. 2005, 103, 165.
28. Deng, X.-M.; Tang, X.-L.; Sun, Y. J. Org. Chem. 2005, 70, 6537.
29. Lacey, J. R.; Anzalone, P. W.; Duncan, C. M.; Hackert, M. J.; Mohan, R. S.
Tetrahedron Lett. 2005, 46, 8507.

30. Li, R.-V.; Nguyen, C.-J. J. Am. Chem. Soc. 2005, 127, 17184.
31. Prakash, G. K. S.; Mathew, T.; Panja, C.; Alconcel, S.: Vaghoo, H.; Do, C.; Olah,
G. A. Proc. Natl. Acad. Sci. USA 2007, 104, 3703.

32. Prakash, G. K. S.; Mathew, T.; Panja, C.; Vaghoo, H.; Venkataraman, K.; Olah,
G. A. Org. Lett. 2007, 9, 179.

33. Heydari, A.; Tavakol, H.; Aslanzadeh, S.; Azarnia, J.; Ahmadi, N. Synthesis 2005,
4, 627.

34. Zhang, Z.; Gao, J.; Xia, J. J.; Wang, G. W. Org. Biomol. Chem. 2005, 3, 1617.
35. Kumar, K. A.; Sreelekha, T. S.; Shivakumara, K. N.; Prakasha, K. C.; Gowda, D.
C. Synth. Commun. 2009, 39, 1332.

48
36. Kim, S.; Park, S.; Bosco, W.; Chidrala, R. K.; Park, J.; Kwon, M. S. J. Org.
Chem. 2002, 74, 2877.

37. Reddy, P. S.; Kanjilal, S.; Sunitha, S.; Prasad, R. B. N. Tetrahedron Lett. 2007,
48, 8807.

38. Kobayashi, Y.; Harayama, T. Org. Lett. 2009, 11, 1603.
39. Landaeta, V. R.; Munoz, B. K.; Peruzzini, M.; Herrera, V.; Bianchini, C.;
Sanchez, D.; Roberto, A. Organometallics 2006, 25, 403.

40. Koren-Selfridge, L.; Londino, H. N.; Vellucci, J. K.; Simmons, B. J.; Casey, C.
P.; Clark, T. B. Organometallics 2009, 28, 2085.

41. Walker, M. A.; Johnson, T. D.; Meanwell, N. A.; Banville, J. PCT Int. Appl. WO
0196283, 2001.

42. Bharucha, K. R.; Cross, C. K.; Rubin, L. J. J. Agric. Food. Chem. 1986, 34, 814.
43. Larsen, J.; Joergensen, A. K. J. Chem. Soc. Perkin. Trans. 1992, 2, 1213.
44. Bach, P.; Albright, A.; Laali, K. K. Eur. J. Org. Chem. 2009, 1961.
45. Schellenberg, K. A. J. Org. Chem. 1963, 28, 3259.

49
3 Chapter 3: Reduction of Carbonyl to Methylene:
Me
2
SiHCl-Ga(OTf)
3
as an Efficient Reductant System

3.1 Chapter 3: Introduction

Environmentally acceptable chemical processes and products are essential
elements for sustainable development.
1
The scientific community is on the lookout for
new sustainable media as well as catalysts for the development of environmentally
benign organic processes along with suitable modifications of many reaction
methodologies. The deoxygenation of aldehydes and ketones to methyl or methylene
derivatives is one of the most often studied transformations in synthetic organic
chemistry.
2
The first example for the reduction of carbonyl compounds to hydrocarbons
was first reported by Clemmensen in 1913 using Zn-Hg and HCl.
3-4
Later, Wolff and
Kishner developed another method for the deoxygenation of carbonyl compound to
methyl or methylene derivatives via hydrazone or semicarbazone cleavage in basic
media.
5-8
Following these revolutionary investigations, other methods have also been
developed, such as catalytic hydrogenation,
9-11
reduction using H
2
/Raney nickel,
12-13
and
reaction involving the use of triisopropylphosphite.
14
All of these methods, while offering
some advantages, also suffer from disadvantages in relation to their general applicability,
selectivity, reaction protocol, toxicity, reaction time and yields.
15-16
Direct catalytic
procedures are also known for the reaction but drastic reaction conditions are required
(150-180 bar, 270-300
0
C).
17
On the other hand, the reduction of aryl aldehydes and
ketones have been successfully performed using metal hydride reagents such as
aluminum hydride,
18-23
boron hydride,
24-31
or hydrosilane
32-39
with the combination of
50
stoichiometric or excess amounts of Lewis or Brønsted acids. However, only few
examples are available for reactions employing catalytic amount of Lewis acids such as
AlCl
3
, BF
3
-Et
2
O, AlBr
3
, etc., or Brønsted acids.
40
Furthermore, most of the strong Lewis
acids are prone to fast hydrolysis and are not reusable in many cases. In contrast, we
have shown that gallium (III) trifluoromethanesulfonate [Ga(OTf)
3
, gallium triflate], acts
as an effective but mild and water tolerant Lewis acid catalyst for many organic synthetic
transformations such as Friedel–Crafts alkylations, dehydration of oximes to the
corresponding nitriles, Beckman rearrangement, etc.
41-48
We also found that gallium
triflate offers the optimum acidity required for ketonic Strecker reaction and the synthesis
of various heterocycles such as dihydrobenzimidazolines, benzothiazolines,
benzoxazinones etc.
49-50
In addition, the fact that this catalyst can be easily recovered and
recycled shows its significant potential as a safe and environmentally benign catalyst.
Inspired by these results, we decided to carry out the carbonyl reduction reaction using
catalytic amount of Ga(OTf)
3
. We found that Ga(OTf)
3
acts as green aqua-stable catalyst
for the activation of various silane reducing agents for the deoxygenation of carbonyl to
methylene in good to excellent yields under mild conditions.

3.2 Chapter 3: Results and Discussion
In the present method, the carbonyl reduction of a variety of ketones to the
corresponding methylenic products has been efficiently carried out under mild conditions
(Scheme 3.1). We have screened the activity of different organosilanes and found that
dimethylchlorosilane (Me
2
SiHCl, DMCS) is the most efficient one under the reaction
conditions. Initially, the reaction has been attempted using 4,4’-dichlorobenzophenone as
51
the substrate and Me
2
SiHCl as the reductant in the presence of 5 mol% Ga(OTf)
3
. This
reaction was chosen as a model reaction for optimization.
R R'
O
Me
2
SiClH +
5 mol% Ga(OTf)
3
CH
2
Cl
2
, rt-60
0
C
R R'
R = alkyl, aryl
R'= alkyl, aryl

Scheme 3.1 Ga(OTf)
3
catalyzed carbonyl defunctionalization reaction

It was found that as a solvent, dichloromethane gave the best result for this
reaction (Table 3.1, entry 1). Chloroform also gave comparable result but with a slightly
lower yield (Table 3.1, entry 3). However, when THF was used as the solvent, only trace
amount of product is detected (Table 3.1, entry 4). The use of CH
3
CN also resulted in a
lower yield due to low solubility of the starting materials (Table 3.1, entry 5). It is
important to note that when the same reaction was carried out without Ga(OTf)
3
, the
reaction did not proceed, only the starting material was recovered (Table 3.1, entry 6).
Various organosilanes were then screened under similar reaction conditions using
dichloromethane as solvent. The carbonyl reduction reaction was found to be feasible
with reductants such as Me
2
SiHCl, Et
3
SiH, polymethylhydro-siloxane (PMHS), and
PhSiH
3
. However, the use of Et
3
SiH, PMHS, or PhSiH
3
instead of Me
2
SiHCl required
longer reaction time and higher temperature for the completion of the reaction (Table
3.1, entry 2, 7 and 9). Though the reactions occur smoothly with 1:2 molar ratio of
ketone:organosilane, a slight excess (2.5 mmol) of organosilane was preferred. Use of
dimethoxy(methyl)silane or 1,1,1,3,5,5,5-heptamethyl-trisiloxane also produced lower
yield (Table 3.1, entry 8 and 10). Consequently, it was found that the Me
2
SiHCl-
52
Ga(OTf)
3
combination in dichloromethane can act as a very efficient carbonyl
deoxygenation system for a series of aryl/alkyl substituted ketones.
Table 3.1 Screening of solvents and organosilane reductants for Ga(OTf)
3
catalyzed
carbonyl defunctionalization reaction
Entry Organosilane Yield (%)
a
1
2
3
4
5
7
c
Me
2
SiClH
Me
2
SiClH
Solvent
95
0
6
b
a
Isolated yield.
b
Reaction done in the absence of Ga(OTf)
3
.
c
Organosilane, 3 mmol used
82
O
Cl Cl
91
(CH
3
O)
2
CH
3
SiH 43
((CH
3
)
3
SiO)
2
CH
3
SiH 75
Ga(OTf)
3
(5 mol%)
solvent, rt-60
0
C
Organosilane
Cl Cl
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
8
9
c
Me
2
SiClH CHCl
3
Me
2
SiClH THF
Me
2
SiClH CH
3
CN
Temp (
0
C)
rt
rt
rt
rt
rt
60
60
60
60
91
trace
79
10
Time (hr)
0.5
0.5
12
6
12
12
12
12
12
1c 2c
Et
3
SiH 89 CH
2
Cl
2
75 12
PMHS
PhSiH
3

The reduction of various carbonyl compounds are summarized in Table 3.2.
Under optimized conditions, the reactions occurred at room temperature in
dichloromethane and were completed smoothly within 2 hrs to give the corresponding
methylene compounds. The Me
2
SiHCl-Ga(OTf)
3
system reduced benzophenone to
53
diphenylmethane in 87% yield (Table 3.2, entry a). The halo, methyl, methoxy, cyano, or
nitro substituted benzophenone were also converted to the corresponding methylene
compounds by this reductant system in good yields (Table 3.2, entry b-i). However,
higher temperature was required for methoxy substituted benzophenone (entry d).
Functional group such as nitro group is unaffected (Table 3.2, entries h, q) while cyano
substitution lead to a mixture resulting in lower yield of the desired reduction product
(Table 3.2, entry g). It is interesting to point out that 4-acetylbenzonitrile was converted
to the corresponding chloride predominantly under similar reaction conditions (Table
3.2, entry r). This system is not only effective for the reduction of aromatic ketones but
also for aliphatic ones albeit in relatively lower yields (Table 3.2, entry l, m). Besides,
this system is also efficient for various polycyclic aromatic substrates (Table 3.2, entry
m-o).

54
Table 3.2 Ga(OTf)
3
catalyzed carbonyl defunctionalization of ketones with Me
2
SiHCl
Entry Substrate Product
Yield (%)
†
Time (h)
a
b
c
d
e
f
g
h
i
j
O
O
Cl
O
Cl Cl
O
H
3
CO OCH
3
O
H
3
C CH
3
O
Cl
Cl
O
Ph
Ph
Ph
Cl
Cl Cl
H
3
CO OCH
3
H
3
C CH
3
Cl
Cl
Ph
Ph
Ph
0.5
95
1 93
2
87
1 97
1 88
#
1
94
1
87
O
F F
NC
O
2
N
O
O
F F
NC
O
2
N
99 0.5
66
89
1.5
1.5
9b

55
Table 3.2 Continued
Entry Substrate Product Yield (%)
a
Time (h)
k
l
m
n
o
p
q
CH
3
O
O
2
N
CH
3
O
Br
CH
3
O
NC
Me
Cl
H
O
O
O
NC
O
CH
3
CH
3
O
2
N
CH
3
Br
CH
3
83 1.25
88 0.5
58 1
CH
3
CH
3
O
63
#
72
#
0.5
0.5
1
r
1.5 95
1.5 89
MeO
MeO
O
CH
3
73 1 s
CH
3
88
†
Isolated yields.
#
Reactions carried out at 60
0
C.

56
In general, the use of Ga(OTf)
3
resulted in the exclusive formation of
deoxygenated product with no deoxygenative chlorination in all cases except for 4-
acetylbenzonitrile.
51
To demonstrate the environmentally friendly character of Ga(OTf)
3
,
a series of carbonyl defunctionalization reactions of adamantanone (1m) have been
carried out with the same catalyst after regeneration following each reaction. After each
reaction the catalyst has been filtered, washed with dichloromethane and reused directly
with required amount of oraganosilane for the next reaction without further purification.
The results indicate that catalyst remains active for further reactions and can be easily
regenerated and recycled.
Mechanistically, this reaction is assumed to proceed by the pathway shown in
(Scheme 3.2), in accordance with the mechanism proposed by Akio Baba and
coworkers.
52
The first step should involve the hydrosilylation of the carbonyl moiety to
give the corresponding silyl ether 3 which is further activated by Ga(OTf)
3
. Reaction with
another molecule of chlorodimethylsilane gives the desired methylene product 2 and the
disilylether 4, with the regeneration of the catalyst after work-up for further reactions.
R R'
O
(TfO)
3
Ga
+
R R'
H
H
SiMe
2
Cl H
R R'
O
H
3
(TfO)
3
Ga
-Ga(OTf)
3
H
SiMe
2
Cl
SiMe
2
Cl
R R'
O
H
3
(TfO)
3
Ga SiMe
2
Cl
1
+
2
+ (Me
2
ClSi)
2
O
4

Scheme 3.2 Proposed reaction pathway

57
3.3 Chapter 3: Conclusion

In summary, we have developed a simple direct deoxygenation reaction of
carbonyl to methylene which employs chlorodimethysilane as the reductant with
Ga(OTf)
3
as a reusable and efficient catalyst. This reducing system is superior to
conventional reducing systems since several functional groups are remarkably tolerant
towards this system and the reactions are highly feasible under very mild conditions
using a water tolerant catalyst in a short reaction time. The simple experimental
procedure, high yields of products and their easy separation, combined with the recovery
and reusability of the catalyst are expected to contribute to the development of a
sustainable strategy for the synthesis of useful building blocks and bioactive molecules.

3.4 Chapter 3: Experimental
3.4.1 General
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. Ga(OTf)
3
was prepared by following a reported procedure.
53
The products were
identified by
1
H,
13
C NMR and GC–MS spectral analysis.
1
H and
13
C NMR spectra were
recorded on 400 MHz Varian NMR spectrometer using CDCl
3
as solvent.
1
H and
13
C
NMR chemical shifts were determined relative to tetramethylsilane (TMS) at δ 0.0 ppm
or to residual solvent peak at δ 7.26 ppm for CDCl
3
.
13
C NMR shifts were determined
relative to TMS at δ 0.0 ppm or to the residual solvent peak (at δ 77.16 ppm for CDCl
3
).
Mass spectra were recorded on a Thermo Finnigan (EI) spectrometer.

58
3.4.2 General Procedure for Ga(OTf)
3
catalyzed carbonyl defunctionalization of
ketones with Me
2
SiHCl.

Ketones (2.0 mmol) dissolved in 4 mL of CH
2
Cl
2
was added to Ga(OTf)
3
(52 mg,
5 mol%) in a pressure tube. Organosilane in excess (5 mmol) was then added to the
reaction mixture and the pressure tube was closed. The mixture was stirred at the
designated temperature until the completion of the reaction (monitored at different time
intervals by TLC and NMR). The mixture was then filtered and the residue was washed
with CH
2
Cl
2
(2 × 5 mL). The combined filtrate was concentrated under reduced pressure
and the product obtained was further purified by trituration of the residue with excess
hexane followed by evaporation of hexane or by flash column chromatography on silica
gel (100% hexanes as eluent) to give the corresponding product.

3.4.3 Spectral Data
All products (except 2i) were known and characterized by comparing their spectral data
with those of the authentic samples.
Spectral data of 2i:
1
H NMR (400 MHz, CDCl
3
): δ = 7.36-7.20 (m, 5H), 7.17-7.14 (m,
2H), 7.03-7.00 (m, 1H), 3.92 (s, 2H).
13
C NMR (100.63 MHz, CDCl
3
): δ = 141.50,
139.86, 132.47, 130.90, 130.46, 130.23, 128.99, 128.82, 128.45, 126.68, 41.12.

59
3.5 Chapter 3: Representative Spectra
Figure 3.1
1
H NMR Spectrum of 2i

ppm (f1)
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
Cl
Cl
60
Figure 3.2
13
C NMR Spectrum of 2i

61

3.6 Chapter 3: References
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63
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42. Prakash, G. K. S.; Yan, P.; Torok, B.; Olah, G. A. Synlett 2003, 527.
43. Prakash, G. K. S.; Yan, P.; Torok, B.; Olah, G. A. Catal. Lett. 2003, 87, 109.
44. Yan, P.; Batamack, P.; Prakash, G. K. S.; Olah, G. A. Catal. Lett. 2005, 101, 141.
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46. Deng, X.-M.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2005, 70, 6537.
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48. Nguyen, R.-V.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 17184.
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50. Prakash, G. K. S.; Mathew, T.; Panja, C, Vaghoo, H.; Venkataraman, K.; Olah, G.
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51. Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2002, 124,
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52. Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett. 1998, 39, 6291.
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64
4 Chapter 4: Trimethylsilyl Trifluoromethanesulfonate as a
Metal-Free, Homogeneous and Strong Lewis Acid Catalyst
for Efficient One-Pot Synthesis of α-Aminonitriles and Their
Fluorinated Analogues

4.1 Chapter 4: Introduction
Fluorinated amino acids are becoming increasingly important in pharmaceuticals
and other biological applications
1-7
such as the development of anticancer drugs for the
control of tumor growth, drugs for the control of blood pressure and allergies.
8
They have
been shown as irreversible inhibitors of pyridoxal phosphate dependent enzymes.
9
Also,
recent studies with fluorinated amino acids have shown the possibilities for the design
and construction of hyperstable protein folds and studies of the protein–protein
interaction for unnatural amino acids.
10-17
Fluorinated amino acids are also a valuable tool
for the screening of protein dynamics by NMR studies.
10-17
Consequently, fluorinated
amino acids have become the object of intense synthetic activity in recent years.
One of the most important and popular approaches towards the synthesis of α-
amino acids via the formation of α-aminonitriles is the multicomponent Strecker
reaction.
18
However, successful three-component Strecker reactions using ketones and
fluorinated ketones are rare.
19-31
We have recently shown
32
that by choosing a proper
catalyst and solvent system (suitable metal triflates as a catalyst and dichloromethane as a
solvent) direct three-component Strecker reactions of ketones can be carried out
successfully, under mild conditions. In our previous study, we have found that gallium
triflate in dichloromethane is the best catalyst–solvent combination for the effective
Strecker reaction of ketones and fluorinated ketones. However, realizing the fact that
65
metal-free organocatalysis
33-40
has drawn considerable interest of chemists in recent times
and metal-free homogeneous catalysis is advantageous for designing suitable drugs
devoid of any metal content, it would be desirable to develop the Strecker reaction of
ketones using metal-free Lewis acid catalysts. Since late 1970s, trimethylsilyl
trifluoromethanesulfonate (TMSOTf)
41-48
is known to be an efficient silylating agent as
well as a strong Lewis acid. Olah et al. have carried out the synthesis of ethers by
efficient reductive coupling of carbonyl compounds using TMSOTf.
49-50
During the last
decade a series of successful synthetic organic transformations has been reported using
TMSOTf as a homogeneous Lewis acid.
51-80
We envisioned TMSOTf as a good metal-
free Lewis acid catalyst and decided to explore its catalytic potential in the direct three-
component Strecker reaction.

4.2 Chapter 4: Results and Discussion
Herein, we report the results for the synthesis of both fluorinated and
nonfluorinated α-aminonitriles from the corresponding ketones and amines with TMSCN
using catalytic amount (5 mol%) of trimethylsilyl triflate in dichloromethane.
The Strecker reaction with aldehydes has been studied extensively with a variety
of catalysts
81-90
including a number of metal triflates.
91-93
However, the reactions were not
feasible for ketones until the development of a mild and efficient method for the direct
three-component Strecker reaction recently, using gallium triflate and the related metal
triflates as catalysts (Table 4.1).
32
Previously, an efficient, clean and direct three-
component Strecker reaction using aromatic ketones and aromatic amines has been
repeatedly cited in the literature as a challenge.
23-24, 81-90

66
Table 4.1 Strecker Reaction of Acetophenone and Aniline Catalyzed by
Trimethylsilyl Triflate and Various Metal Triflates
a

Entry Catalyst Yield (%)
b
1
2
3
4
5
6
7
8
9
TMSOTf
Ga(OTf)
3
Yb(OTf)
3
Y(OTf)
3
Sc(OTf)
3
Sm(OTf)
3
La(OTf)
3
Cu(OTf)
3
NdGa(OTf)
3
86
98
92
85
89
90
75
80
75
c
a
Time: 5h; amount of catalyst: 5 mol%
b
Isolated yield
c
Determined by NMR analysis

Quite often these reactions have to be carried out stepwise (preparation of imines
first followed by cyanide addition)
19-20
or under high-pressure conditions.
23-24
Use of
ammonia or ammonium salts in the presence of cyanides has been described.
25-30
During
our search for an effective homogeneous, metal-free Lewis acid catalyst, we found that
TMSOTf is also capable of catalyzing the direct three-component Strecker reaction
successfully. The results show that it has a similar effect as the metal triflate catalysts
(Table 4.1).
67
We have explored the role and efficacy of TMSOTf as a catalyst towards the
Strecker reaction of various aldehydes, ketones, and their fluorinated analogues with
various amines under similar conditions (Scheme 4.1). The reaction is found to be clean,
simple and in all cases high yields of the nitrile products were obtained, except in the
case of benzophenone, which required higher temperature and excess of TMSCN to
afford the desired α-aminonitrile (Table 4.2, entry 11). However, reactions with aliphatic
amines under ambient conditions led to mixtures.
R
1
O
R
2
Ar NH
2
CN
N
R
1
R
2
Ar
H
TMSCN
TMSOTf
CH
2
Cl
2
, r.t.
+ +
R
1
= aryl, alkyl
R
2
= H, alkyl

Scheme 4.1 TMSOTf-catalyzed Strecker reaction using aldehydes/ketones and amines

One of the key factors for the success of this reaction is introduction of
dichloromethane as the solvent. In earlier studies,
41-48, 51-80
acetonitrile and toluene were
used as solvents, which are, however, not suitable for the direct Strecker reaction of
ketones due to their interaction with the catalyst. Use of dichloromethane minimizes
such interaction resulting in enhanced catalytic activity of the catalyst towards ketones
providing a suitable environment for the reaction.

68
Table 4.2 TMSOTf-Catalyzed Strecker Reaction Using Different Aldehydes/Ketones and
Amines
Entry Ketone/aldehyde Amine Product Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
10
11
Cl
CHO
Cl
CHO
CHO
Cl
CHO
Me
O
Me
O
Me
O
Me
O
Br
Me Me
O
O
O
H
2
N
H
2
N
H
2
N
Me
H
2
N
Cl
H
2
N
H
2
N
Me
H
2
N
Br
H
2
N
H
2
N
Me
H
2
N
H
2
N
Cl
N
H CN
H
N
H CN
H
Cl
N
H CN
H
Me
Cl
N
H CN
H
Cl
N
Me CN
H
N
Me CN
H
Me
N
Me CN
H
Br
N
Me CN
H
Br
Me N
Me
CN
H
Me
N
CN
H
N
CN
H
6 73
6 75
6 75
6 87
6 73
6 87
6 86
3 90
3 83
3 86
3 87

69
Encouraged by these results and realizing the importance of fluorinated molecules
in chemistry,
94-101
we extended our methodology to fluorinated ketones (Scheme 4.2).
We found that mono-, di-, and trifluoromethylated aliphatic ketones react smoothly with
a variety of amines under mild conditions to provide the corresponding fluorinated α-
aminonitriles in high yield and purity. One of the significant aspects of this methodology
is that we can incorporate a monofluoro, difluoro, or trifluoromethyl moiety in the α-
aminonitrile product by simply varying the nature of the fluorinated ketones.
H
3
C
O
R
3
R
1
R
2
Ar NH
2
TMSCN
TMSOTf
CH
2
Cl
2
, r.t., 6 h
+ +
R
1
R
3
R
2
H
3
C
N
NC
H
Ar
R
1
, R
2
, R
3
= H, F

Scheme 4.2 TMSOTf-catalyzed Strecker reaction of fluorinated ketones

However, it is interesting to note that with aromatic trifluoromethyl ketones such
as 1,1,1-trifluoroacetophenone, instead of the expected three-component reaction
products, the TMS-protected fluorinated cyanohydrin derivative (TMSCN addition
product from 1,1,1-trifluoroacetophenone) was obtained. Probably in the case of the
aliphatic fluorinated ketones, the rate of initial aminal/imine formation is fast compared
to the rate of the cyanohydrin adduct formation and subsequently the desired products
from three-component reaction were formed predominantly as in the case of Ga(OTf)
3
-
catalyzed direct Strecker reaction of ketones. Table 4.3 shows the results of the Strecker
reaction for different fluorinated ketones and a variety of amines. This present
methodology does not need further purification of the products, thus avoiding further
chromatography and product loss during purification. The products are obtained in very
high yield and purity.
70
Table 4.3 TMSOTf-Catalyzed Strecker Reaction of Mono-, Di-, and Trifluoromethyl
Ketones
Entry Ketone Amine Product Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
FH
2
C Me
O
FH
2
C Me
O
FH
2
C Me
O
HF
2
C Me
O
HF
2
C Me
O
HF
2
C Me
O
F
3
C Me
O
F
3
C Me
O
F
3
C Me
O
H
2
N
H
2
N
Me
H
2
N
Br
H
2
N
H
2
N
Me
H
2
N
Br
H
2
N
H
2
N
Me
H
2
N
Br
FH
2
C N
Me
CN
H
FH
2
C N
Me
CN
H
Me
FH
2
C N
Me
CN
H
Br
HF
2
C N
Me
CN
H
HF
2
C N
Me
CN
H
Me
HF
2
C N
Me
CN
H
Br
F
3
C N
Me
CN
H
F
3
C N
Me
CN
H
Me
F
3
C N
Me
CN
H
Br
6
6
6
6
6
6
6
6
6
84
74
83
82
99
79
73
72
79

71
4.3 Chapter 4: Conclusion
In summary, the application of trimethylsilyl triflate as an effective metal-free,
homogeneous, and strong Lewis acid catalyst for the Strecker reaction has been
demonstrated. Our studies show that not only aldehydes but also ketones and fluorinated
ketones can efficiently undergo the Strecker reaction under very mild conditions using
trimethylsilyl triflate as a catalyst in dichloromethane. Like various metal triflates,
trimethylsilyl triflate also shows good catalytic activity for the Strecker reaction of
ketones. Simple and clean reaction, high yields, and high purity of the products are the
salient features of this methodology. This methodology is applicable for a wide range of
substrates, thus making it a versatile route for the α-aminonitrile synthesis. Studies are
under way to render the reaction stereoselective by employing chiral ligands in
conjunction with various metal and metal-free triflate Lewis acid catalysts.

4.4 Chapter 4: Experimental
4.4.1 Materials and Methods
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. The products were characterized by analyzing their spectral data and comparing
them with those of the authentic samples.
32

1
H,
13
C, and
19
F NMR spectra were recorded
on 400 MHz Varian NMR spectrometer using CDCl
3
as solvent.
1
H and
13
C NMR
chemical shifts were determined relative to tetramethylsilane (TMS) at δ 0.0 ppm or to
residual solvent peak at δ 7.26 ppm for CDCl
3
.
13
C NMR shifts were determined relative
to TMS at δ 0.00 ppm or to the residual solvent peak (at δ 77.16 ppm for CDCl
3
).
19
F
NMR chemical shifts were determined relative to internal standard CFCl
3
at δ 0.00 ppm.
72
4.4.2 General Procedure for the Strecker Reaction of Aldehydes and Ketones

Aldehyde or ketone (2 mmol)/fluorinated ketone (3 mmol), amine (2 mmol),
TMSCN (3 mmol), and TMSOTf (5 mol%) were taken in CH
2
Cl
2
(5 mL) in a sealed
pressure tube and the reaction mixture was stirred at r.t. for several hours. Completion of
the reaction was monitored by NMR. After completion, the reaction mixture was
quenched with H
2
O and then extracted with CH
2
Cl
2
(3 × 15 mL). All the organic layers
were collected, washed with brine solution, and dried over anhyd Na
2
SO
4
. Removal of
the solvent under reduced pressure provided the crude products. The crude product was
triturated with excess hexanes for several times and removal of the solvents under
reduced pressure afforded the Strecker product (α-aminonitriles) in almost analytically
pure form (by NMR).

73
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100. Peters, R. Carbon-Fluorine Compounds Chemistry, Biochemistry and Biological
Activities; Ciba Foundation Symposium, Elsevier: Amsterdam, 1972.

101. Walsh, C. T. Annu. Rev. Biochem. 1984, 53, 493.
79
5 Chapter 5: Efficient One-Pot Synthesis of Novel
Fluorinated Heterocycles Using Trimethylsilyl
Trifluoromethanesulfonate as a Metal-Free Homogeneous
Lewis Acid Catalyst

5.1 Chapter 5: Introduction
Heterocyclic compounds such as benzimidazolines, benzothiazolines,
benzoxazolines, dihydrobenzoxazinones, 1,2,3,4-tetrahydroquinazolines, 4H-3,1-
benzoxazines and 3,1-benzoxathiin-4-ones are important classes of compounds.
Benzimidazolines, often referred to as organic hydrides, can act as good reducing agents
and good hydrogen storage materials in many organic reactions.
1-4
Benzothiazolines and
benzoxazolines are used as plant growth régulants, herbicides, anticonvulsants, in
photochromic dyes and for the treatment of ADD (Attention Deficiency Disorder).
5-6

Dihydrobenzoxazinones are used in analgesics and also as useful building blocks for
drugs and pharmaceuticals, which possess antiviral, antifungal, antibacterial and
antiparasitic properties.
7-8
1,2,3,4-Tetrahydroquinazolines, 4H-3,1-benzoxazines and 3,1-
benzoxathiin-4-ones also show similar biological activities.
9-14
In addition, 4H-3,1-
benzoxazines are used in lithium ion batteries,
15
as anti-knock agent for gasoline,
16
and as
stabilizers, especially for jet fuels and turbine fuels.
17

Fluorinated heterocycles are becoming increasingly important in the
pharmaceutical industry and development of new reaction methodologies for their
convenient and efficient synthesis has attracted the efforts of a large number of synthetic
chemists in recent years. It is well known that the presence of fluorine can result in
substantial functional changes in the biological as well as physicochemical properties of
80
organic compounds.
18-25
Incorporation of fluorine into drug molecules can highly affect
their physicochemical properties, such as bond strength, lipophilicity, bioavailability,
conformation, electrostatic potential, dipole moment, pKa etc; pharmacokinetic
properties, such as tissue distribution, rate of metabolism; and pharmacological
consequences, such as pharmacodynamics and toxicology. Considering the increasing
importance of fluorinated heterocycles and knowing the effect of fluorine substitution, we
became interested in synthesizing the fluorinated analogs of the abovementioned classes
of compounds.
Recently,
26
we have shown that gallium triflate in dichloromethane is one of the
best catalyst-solvent combination for the effective condensation-cyclization reaction of
fluorinated ketones with ortho-aniline derivatives for the synthesis of fluorinated
heterocycles such as fluorinated benzimidazolines 7a, benzothiazolines 7b,
benzoxazolines 7c, and dihydrobenzoxazinones 8. However, cognizant of the fact that
metal-free organocatalysis
27-34
has drawn considerable attention of chemists in recent
times and metal-free homogeneous catalysis is highly significant and advantageous for
designing suitable drugs completely devoid of any metal content, we realized it would be
very useful to perform similar reactions using metal-free Lewis acid catalysts.
Since the late 1970s, trimethylsilyl trifluoromethanesulfonate (TMSOTf) is known
to be an efficient silylating agent as well as a strong Lewis acid.
35-42
In the late 1980s our
group has successfully carried out the reductive coupling of ketones, to produce the
corresponding symmetrical ethers using TMSOTf as the catalyst.
43-44
In the last decade,
varieties of organic transformations, including Friedel-Crafts reactions, Diels-Alder
reactions, C-O couplings, epimerizations etc. have been carried out successfully using
81
TMSOTf as a homogeneous Lewis acid catalyst.
45-75
Recently, we have accomplished the
direct three component Strecker reaction of aldehydes, ketones and fluorinated ketones
using TMSOTf as the catalyst.
76
Considering all these facts, we surmised that TMSOTf
can act as a good metal-free, homogeneous Lewis acid catalyst for the condensation-
cyclization reaction of various bifunctional arenes with aldehydes and ketones. Also, in
our previous studies we have shown that the synthesis of four different kinds of
fluorinated heterocycles from aniline derivatives can be carried out using gallium triflate
as the catalyst. In our current studies, we succeeded in expanding our methodology to
other possible 1,2-disubstituted benzene derivatives such as thiosalicylic acid, anthranilic
acidamides, o-hydroxybenzyl amine, etc., showing the versatility of this condensation-
cyclization methodology. Hence we could easily prepare 3,l-benzoxathiin-4-ones 12 and
similar derivatives under relatively mild conditions. Herein, we report in detail the results
of our studies for the efficient synthesis of many previously unknown fluorinated
heterocycles using catalytic amounts of trimethylsilyl triflate as the Lewis acid catalyst.

5.2 Chapter 5: Results and Discussion
5.2.1 Synthesis of Fluorinated Benzimidazolines, Thiazolines, Oxazolines and
Oxazinones

Benzimidazolines 3 are generally synthesized from the reaction of 1,2-
phenylenediamines 1 and benzaldehyde (Scheme 5.1).
77-80
However, when ketones (R
1
,
R
2
= alkyl, phenyl) were used under similar conditions, 1,5 benzodiazepine derivatives 4
were formed as the major products (Scheme 5.1).
81-86
This reaction proceeds through the
diimine intermediate 10a (Scheme 5.3), which then undergoes an internal Michael type
82
addition reaction to give rise to the corresponding 1,5-benzodiazepine derivatives 4
(Scheme 5.1).
NH
2
NH
2
1
R
1
, R
2
= Alkyl, Phenyl
4
Y
Ph H
O
Ph CH
2
R
2
O
Y
N
N
CH
2
Ph
Ph
Y
N
N
H
R
1
R
2
R
1
CH
2
R
2
2
+
Y
N
H
N
CH
2
Ph
H
Ph
3

Scheme 5.1 Reactions of benzaldehyde and ketones with 1,2–phenylenediamines

Reports on the direct synthesis of fluorinated benzimidazolines are very rare.
87-88

To our best knowledge, an easy and convenient method was not available until we
recently communicated our preliminary results on condensation-cyclization.
26
Funabiki et
al.
89
have prepared fluorinated benzimidazolines from fluorinated alkynyl carboxylic
acids 5 (Scheme 5.2). Synthesis of more diverse and functionalized starting materials for
this reaction is tedious. Since the reaction conditions and chemical yields are not very
impressive in all cases, finding a convenient and efficient method feasible under ambient
conditions has been an important goal.
83
5
NH
2
XH
N
H
X
CH
3
R
f
N
H
X
CH
2
COOH
R
f
N
H
XH COOH
R
f N
XH COOH
R
f
N
H
H
N
NH
2
NH
2
CH
3
R
f
C C R
f
COOH
EtOH, H2O
Reflux, 1-32h
X = NH, S, O
Rf = CHF
2
, CHF
2
CF
2
CF
2
, CF
3
+
EtOH, H2O
Reflux, 7-20h
22-88 %
52-78 %
5
6
C C R
f
COOH +

Scheme 5.2 Synthesis of fluorinated benzimidazolines from fluorinated alkynyl
carboxylic acids and vicinal-diamines

We explored the synthesis of fluorinated benzimidazolines directly from
fluorinated ketones and diamines using gallium triflate as the Lewis acid catalyst
(Scheme 5.3). In our previous communication
26
we have discussed the results of our
studies. We found that Ga(OTf)
3
is a very unique and highly efficient catalyst for this
transformation under mild conditions. High efficiency and greater versatility of this
reaction, including high selectivity and purity of the products, reveal the significance of
using Ga(OTf)
3
as a highly suitable catalyst for these reactions.
It is clear from our earlier results that the number of fluorine atoms present in the
fluorinated ketone has a significant governing effect on the path of the reaction. This is
because the electrophilicity at the carbon center of the monoimine intermediate 9 depends
strongly on the number of fluorine atoms attached to the α-carbon. An increase in the
84
number of fluorine atoms significantly increases the electrophilicity at the carbon center
of the monoamine intermediate. Because of this the non-bonding electron pair on the
nitrogen atom of the second amino group rapidly attacks the highly electrophilic carbon
center of the internal fluorinated imine. This is followed by a 1,3-proton transfer, which
leads to the formation of the corresponding 5-membered ring (Scheme 5.3).
On the other hand, when the number of fluorine atoms in the ketone drops to one
or zero, the electrophilicity at the carbon center of the monoimine 9a is not sufficient to
facilitate internal attack by the electron pair on the nitrogen atom of the second amino
group. Thus, the second amine moiety reacts faster with another molecule of ketone to
form the diimine intermediate 10a, which undergoes further rearrangement to give rise to
the corresponding 7-membered ring (Scheme 5.3).

85
XH
NH
2
1a
4
XH
N
N
N
CH
2
R
2
R
1
NH
2
NH
2
N
NH
2
9a
H
N
N
Y
CH
2
R
2
R
1
R
2
R
1
10a
Y
R
1
Rf
O
Y
R
1
Rf
R
1
CH
2
R
2
CH
2
R
2
R
1
1 9
7
R
1
CH
2
R
2
O
R
1
CH
2
R
2
O
Tautomerism
Cyclization
1,3-H
+
transfer
Formation of seven-membered ring
Formation of five-membered ring
Y
N
H
X
R
1
Rf
Y
N
X
R
1
Rf
H
Y
Y Y
Y
N
N
H
R
1
R
2
R
1
CH
2
R
2
Y
N
N
R
1
R
2
R
1
H
CH
2
R
2

Scheme 5.3 Mechanism of the formation of five and seven membered ring

86
Our detailed investigation on the potential of other metal triflate catalysts towards
this condensation-cyclization reaction shows that most of the metal triflate catalysts bring
out this reaction efficiently when dichloromethane is used as solvent, except for
lanthanum triflate (Table 5.1, entry 6). However, gallium triflate was found to be
superior, giving the maximum yield of 2-trifluromethylbenzimidazoline (Table 5.1, entry
1). During our search for a metal free, homogeneous and efficient organocatalyst for
these reactions, we found that trimethylsilyl triflate can serve this purpose effectively
(Table 5.1, entry 8). In reactions which require the complete absence of metal catalysts
(strong interaction of metal catalysts with other functional groups by chelation and
complex formation can cause significant decrease in reactivity), trimethylsilyl triflate is
found to be an ideal substitute. The homogeneous nature of this organocatalyst in organic
media is an added advantage, as already mentioned. We have explored the potential of
the catalyst by carrying out a similar study for the condensation-cyclization reaction as
we did in the case of reactions catalyzed by metal triflates (Scheme 5.4). Our present
work also involves the successful extension of this methodology beyond the synthesis of
the four classes of fluorinated heterocycles that were covered in our previous
communication.
26

87
Table 5.1 Reaction of 1,2-phenylenediamine with 1,1,1-trifluoroacetone using various
metal triflates and TMSOTf as the catalysts
Entry Catalyst Yield (%)
1
2
3
4
5
6
7
8
Ga(OTf)
3
Yb(OTf)
3
Y(OTf)
3
Sc(OTf)
3
Sm(OTf)
3
La(OTf)
3
Cu(OTf)
3
TMSOTf
97
93
87
96
88
32
75
92

XH
NH
2 Y
1
Rf R
O
7
5 mol % TMSOTf
CH
2
Cl
2
, rt-120
0
C
Y = H, CH
3
, Cl
X = NH (7a), O (7b), S(7c)
R = alkyl, aryl; R
f
= fluoroalkyl
Y = H
X = COO
R = alkyl, aryl; R
f
= fluoroalkyl
+
6
8a
Y
N
H
X
R
Rf
Y
N
H
O
O
R
Rf

Scheme 5.4 Condensation of ketones with o-amimoarenes using TMSOTf as catalyst
88
When the condensation-cyclization reaction was carried out with the diamine
derivatives and fluorinated ketones using TMSOTf, the results were found to be similar
as in the gallium triflate catalyzed reactions. However, the reaction conditions and yields
of the products were slightly different. 1,2-Phenylenediamines bearing electron
withdrawing and electron donating groups reacted with aliphatic, aromatic and benzylic
trifluoromethyl ketones under TMSOTf catalyzed conditions. In all cases, yields of the
products were found to be high (Table 5.2). As with the gallium triflate-catalyzed
reaction, higher temperature and more reaction time were required for the reaction of
1,1,1- trifluoromethylacetophenone using TMSOTf as the catalyst (Table 5.2, entry 7).
Fluorinated thiazolines 7b, oxazolines 7c and oxazinones 8a (Scheme 5.4) were
also prepared using the corresponding o-amino derivatives and trimethylsilyl triflate as
the catalyst (Table 5.3). 1,1-Difluoroacetone also gave clean products with many of these
o-amino derivatives. In general, it has been found that reactions using anthranilic acid
(Table 5.3, entries 8 and 9) or aromatic trifluoromethyl ketones (Table 5.3, entries 1, 2
and 7) require higher temperatures. On the other hand, when the substrates were changed
to o-aminophenol/o-aminothiophenol and difluoromethyl ketone (Table 5.3, entries 4-6)
reactions proceeded smoothly under very mild conditions. Similar to the gallium triflate
catalyzed reactions, monofluoroacetone always gave a mixture of the corresponding
seven and five membered ring systems (Scheme 5.3, R = F).
26

89

Table 5.2 Preparation of 2-fluoroalkyl benzimidazolines using TMSOTf as the catalyst
amine
fluorinated ketone product time (h)
yield (%)
entry temp (
0
C)
NH
2
NH
2
H
3
C CF
3
O
4 50
N
H
H
N
CH
3
CF
3
70 1
2
NH
2
NH
2
H
3
C CF
3
O
4 50
N
H
H
N
CH
3
CF
3
85
H
3
C
H
3
C
3
NH
2
NH
2
H
3
C CF
3
O
4 50
N
H
H
N
CH
3
CF
3
78
Cl Cl
4
NH
2
NH
2
CF
3
O
4 50
N
H
H
N
CF
3
78
H
3
C
CH
3
5
NH
2
NH
2
CF
3
O
4 50
N
H
H
N
CF
3
80
H
3
C
H
3
C
H
3
C
CH
3
6
NH
2
NH
2
CF
3
O
4 50
N
H
H
N
CF
3
87
7
NH
2
NH
2
CF
3
O
120
N
H
H
N
CF
3
89 5

90
Table 5.3 Preparation of fluorinated benzothiazolines, benzoxazolines and
dihydrobenzoxazinones using using TMSOTf as the catalyst
amine fluorinated ketone product time (h)
yields (%)
entry
temp (0C)
H
3
C CF
3
O
4 75
N
H
O
CH
3
CF
3
87 1
2
CF
3
O
4 75
N
H
O
CF
3
75
3
H
3
C CF
2
H
O
4 rt
N
H
O
CH
3
CF
2
H
78
4
SH
NH
2
H
3
C CF
3
O
6 rt
N
H
S
CH
3
CF
3
88
5
CF
3
O
4 50
N
H
S
CF
3
82
H
3
C
CH
3
6 4 rt
N
H
S
CH
3
CF
2
H
90
7
CF
3
O
100
N
H
S
CF
3
80 4
OH
NH
2
OH
NH
2
H
3
C
CH
3
OH
NH
2
SH
NH
2
SH
NH
2
SH
NH
2
NH
2
COOH
NH
2
COOH
8
9
H
3
C CF
2
H
O
H
3
C CF
3
O
H
3
C CF
2
H
O
7
7
100
75
O
H
N
O
CH
3
CF
3
O
H
N
O
CH
3
CF
2
H
66
70

91
5.2.2 Synthesis of 1,2,3,4-tetrahydroquinazolines, 4H-3,1-benzoxazines and 3,1-
benzoxathiin-4-ones

Syntheses of various other important classes of heterocycles such as 1,2,3,4-
tetrahydroquinazolines 8b, 2,3-dihydro-4(1H)-quinazolinones 8c, 4H-3,1-benzoxazines
8d, and 3,1-benzoxathiin-4-ones 12 have been achieved in good yields by further
extension of the present methodology (Schemes 5.5 and 5.6 and Tables 5.4 and 5.5).
This makes their access easier compared to previous methods. As mentioned earlier,
many of these compounds possess interesting biological activities. Hence building a
library of new fluorinated analogs of such compounds and studying their biological
activities and their potential uses in the pharmaceutical arena would be of great interest.

XH
NH
2
1
R
f
R
O
+
6
5 mol % TMSOTf
CH
2
Cl
2
, rt-120
0
C
X = CH
2
NH (8b), C(O)NH (8c), CH
2
O(8d)
R = alkyl, aryl; R
f
= fluoroalkyl
N
H
X
R
R
f
8

Scheme 5.5 Syntheses of 1,2,3,4-tetrahydroquinazolines 8b, 2,3-dihydro-4(1H)-
quinazolinones 8c, and 4H-3,1-benzoxazines 8d using TMSOTf as the catalyst

Anthranilic acid and the corresponding amides were less reactive and required
higher temperature for higher conversion (Table 5.3, entries 8-9 and Table 5.4b, entries
1-4). 2-Aminobenzyl amine and its hydroxy analog also undergo the condensation-
cyclization reaction with fluorinated ketones to yield the corresponding fluorinated 6-
membered heterocycles in high yields (Table 5.4a, entries 1-7). However, reactions with
aromatic and benzylic trifluoromethyl ketones were found to be sluggish.
92

Table 5.4a Preparation of fluorinated 1,2,3,4-tetrahydroquinazolines and 4H-3,l-
benzoxazines using TMSOTf as the catalyst
amine fluorinated ketone product time (h)
yield (%)
entry
temp (
0
C)
NH
2
H
3
C CF
3
O
12 50 84 1
2 12 50 75
3 12 75 86
4
CF
3
O
3 rt 75
H
3
C
5 2 50 60
6
CF
3
O
3 rt 79
7 rt 73 4
NH
2
CF
3
O
H
3
C
H
3
C CF
3
O
H
3
C CF
2
H
O
H
3
C CF
2
H
O
NH
2
NH
2
NH
2
NH
2
NH
2
NH
2
NH
2
OH
NH
2
OH
NH
2
OH
N
H
NH
CH
3
CF
3
N
H
NH
CH
3
CF
3
N
H
NH
CF
3
N
H
NH
CH
3
CF
2
H
N
H
O
CH
3
CF
3
N
H
O
CH
3
CF
3
N
H
O
CH
3
CF
3

93
Table 5.4b Preparation of fluorinated 2,3-dihydro-4(lH)-quinazolinones using TMSOTf
as the catalyst
amine fluorinated ketone product time (h)
yields (%)
entry
temp (
0
C)
NH
2
H
3
C CF
3
O
12 100 85 1
2
12 100 83 3
12 120 76 4
3 60 86
CF
3
O
NH
2
CF
3
O
H
3
C
H
3
C CF
2
H
O
NH
2
NH
2
NH
2
NH
2
NH
2
NH
2
N
H
NH
CF
3
CH
3
N
H
NH
CH
3
CF
3
N
H
NH
CF
3
N
H
NH
CF
2
H
CH
3
O
O
O
O
O
O
O
O

Reaction of thiosalicylic acid (11) gave the corresponding fluorinated
oxathiinones 12 in good yield and purity showing the synthetic utility and versatility of
this method (Scheme 5.6 and Table 5.5). Hence the scope of this methodology can be
broadened to a greater spectrum despite low conversions and yields for the reaction of
salicylic acid itself. The acidity of TMSOTf as a Lewis acid may not be sufficient to
carry out the condensation-cyclization reaction of salicylic acid successfully.
SH
COOH
11
R
f
R
O
+
6
R = alkyl, aryl; R
f
= fluoroalkyl
S
R
Rf
O
O
12
5 mol % TMSOTf
CH
2
Cl
2
, 75-120
0
C

Scheme 5.6 Synthesis of 3,1-benzoxathiin-4-ones 12 using TMSOTf as the catalyst
94
Table 5.5 Preparation of fluorinated 3,l-benzoxathiin-4-ones using TMSOTf as the
catalyst
amine fluorinated ketone product time (h)
yields (%)
entry
temp (
0
C)
H
3
C CF
3
O
12 100 75 1
2
12 100 91 3
12 120 65 4*
12 75 80
CF
3
O
CF
3
O
H
3
C
H
3
C CF
2
H
O
SH
COOH
SH
COOH
SH
COOH
SH
COOH
SH
COOH
CF
3
O
6 75 96 5
O
S
O
CF
3
CH
3
O
S
O
CF
3
O
S
O
CF
3
O
S
O
CF
2
H
CH
3
CH
3
O
S
O
CF
3
*Unreacted acid was removed by bicarbonate treatment

Interestingly, when 2-hydroxythiophenol (13) was subjected to the condensation-
cyclization reaction under TMSOTf conditions, instead of the desired intramolecular
cyclization, the corresponding intermolecular dithioether formation took place (Scheme
5.7). Thiols are known to undergo similar reactions under acid catalyzed conditions.
90

Since the nucleophilicity of the thio group is greater than that of the hydroxyl group,
formation of thioketal is preferred rather than ketal formation. Further condensation of
thioketal with another molecule of 2-hydroxythiophenol at the thio function gives rise to
the product 14. Therefore, in this case, we did not observe the formation of the expected
cyclized product 15.
95
S S
CF
3
CF
3 OH
S S
CF
3
CF
3 SH
XH
YH
CH
3
F
3
C
O
+
B
B
A 13: X = O; Y=S
16: X=Y=S 18: X=Y=O
A = TMSOTf, CH
2
Cl
2
, 100
0
C, 8h
B = TMSOTf, CH
2
Cl
2
, 50
0
C, 6h
Mixture of products
15 14
17
Major
+
Mixture of products
OH
S
O
CF
3
CH
3
SH

Scheme 5.7 Condensation of ketones with 13, 16 and 18 using TMSOTf as catalyst

For further investigation, we performed the reaction with 1,2-benzenedithiol 16
and catechol 18 under similar conditions (Scheme 5.7). When dithiol 16 was subjected to
similar treatment, a significant amount of product 17 was observed (by NMR) in the
reaction mixture. However, catechol 18 never gave a clean reaction, resulting in complex
mixture of products.
These results prompted us to reinvestigate the mechanism of these reactions
further. In our previous studies, a mechanism involving mainly a monoamine
intermediate has been suggested for the formation of the heterocycles from the o-amino
substrates (Scheme 5.3). However, considering all the current studies and observation of
the formation of the intermolecular reaction product, we now also consider the "aminal"
route. The reaction has been repeated with N-methy-1,2-phenylenediamine 19 with the
96
view that the methyl group should make the amino group attached to it more nucleophilic
than the other amino group favoring the initial aminal formation at the methylamino
function. The initial attack of the amino function can give rise to the aminal intermediate
20, which on activation by the Lewis acid can then undergo either an intermolecular or
intramolecular attack depending on the nature of the other nucleophile (Scheme 5.8). In
the case of compound 19, we obtained the cyclized product 21 only (Scheme 5.8a).
The formation of product 14 from 2-hydroxythiophenol (13) can also be
explained on the basis of this "aminal" type mechanism. Intermolecular attack on the
aminal type of intermediate 22 could give rise to product 14 with the elimination of one
molecule of water (Scheme 5.8b). Since the C-O bond cleavage is more feasible than S-C
(aromatic) bond cleavage under the reaction conditions, product 14 is formed resulting
from the C-O bond cleavage. In the case of 16 and 18, the situation may be more
complicated and thus a complex mixture of products was formed.
97
NH
NH
2
CH
3
N
NH
2
H
3
C
O
R
f
R
1
N
NH
2
CH
3
OH
R
f
R
1
N
H
N
R
1
R
f
N
N
R
1
R
f
H
H
CH
3
H
R
1
O
R
f
LA
LA
HO LA
CH
3
19 20
21
SH
OH
H
S
OH
O
R
f
R
1
S
OH
OH
R
f
R
1
N
H
N
R
1
R
f
R
1
O
R
f
LA
LA
CH
3
13 22
14
HS
HO
S
OH
S
H
HO
R
1
R
f
HO LA
(a) The "aminal" route
(b) Formation of product 14 following the "aminal" type route

Scheme 5.8 Modified mechanism
98
5.3 Chapter 5: Conclusion
Syntheses of various fluorinated heterocycles such as benzimidazolines,
benzothiazolines, benzoxazolines, dihydrobenzoxazinones, 1,2,3,4-
tetrahydroquinazolines, 4H-3,1-benzoxazines and 3,1-benzoxathiin-4-ones were achieved
under mild conditions using TMSOTf, an effective metal-free, homogeneous Lewis acid
catalyst. Even when used in catalytic amounts, this reagent provides the optimum Lewis
acidity required for the synthesis of fluorinated heterocycles. This current methodology
can be considered as a general procedure for the efficient synthesis of many of the above
mentioned heterocycles under metal-free conditions. In most cases, reactions are clean
and easy to work up, require mild conditions and provide the corresponding products in
high yield and purity. The current study also highlights detailed mechanistic aspects of
the condensation-cyclization reaction.

5.4 Chapter 5: Experimental
5.4.1 General
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources.
1
H,
13
C, and
19
F NMR spectra were recorded on 400 MHz Varian NMR
spectrometer using CDCl
3
as solvent.
1
H and
13
C NMR chemical shifts were determined
relative to tetramethylsilane (TMS) at δ 0.0 ppm or to residual solvent peak at δ 7.26 ppm
for CDCl
3
.
13
C NMR shifts were determined relative to TMS at δ 0.00 ppm or to the
residual solvent peak (at δ 77.16 ppm for CDCl
3
).
19
F NMR chemical shifts were
determined relative to internal standard CFCl
3
at δ 0.00 ppm.
99
5.4.2 General procedure for the TMSOTf catalyzed cyclization-condensation
Fluorinated ketone (3 mmol) and o-amine derivative (2 mmol) were placed in a
pressure tube and dissolved in 4 mL of CH
2
C1
2
. To this mixture was added TMSOTf (22
mg, 5 mol%) and the pressure tube was closed. The mixture was stirred at the required
temperature till the completion of the reaction, with monitoring at different time intervals
by TLC and NMR. The mixture was then quenched with water and extracted with
CH
2
C1
2
(3x15 mL). All the organic layers were collected, washed with brine solution (15
mL), dried over anhydrous Na
2
S0
4
and then the solvent was removed under reduced
pressure to obtain the product in NMR pure grade in most cases. Further purification can
be carried out by trituration of the residue with excess hexane followed by evaporation of
hexane or by column chromatography using 4:1 hexane-ethyl acetate solvent mixture.
Products were fully characterized by spectral analysis (
1
H,
13
C,
19
F NMR and HRMS
data) and comparison of the spectral data with those of the authentic samples [9,21].
5.4.3 Spectra Data
2-Methyl-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline (Table 5.4a, entry 1)

1
H NMR δ 1.49 (q, J = 1.21 Hz, 3H), 1.87 (brs, 1H), 3.87 (d, J = 16.61 Hz, 1H), 4.03 (d, J
= 16.67 Hz, 1H), 4.08 (brs, 1H), 6.54 (dd, J = 8.00, 0.87 Hz, 1H), 6.72 (dt, J = 7.41, 1.14
Hz, 1H), 6.92 (dd, J = 7.48, 0.83 Hz, 1H), 7.05 (dt, J = 8.06, 1.61 Hz, 1H);
13
C NMR δ
22.7, 42.3, 68.2 (q, J
2
C-F = 28.83 Hz), 114.7, 118.4, 120.1, 125.52 (q, J
1
C-F = 287.4 Hz),
125.78, 127.5, 140.4;
19
F NMR δ -82.46; HRMS (EI) m/z 216.0878, calculated for
C
10
H
11
F
3
N
2
216.0874.

100
2-Ethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline (Table 5.4a, entry 2)
1
H NMR δ 0.93 (dd, J = 7.86, 7.21 Hz, 3H), 1.92-1.69 (m, 3H), 3.81 (d, J = 16.33 Hz,
1H), 4.00 (s, 1H), 4.04 (d, J = 16.45 Hz, 1H), 6.53 (dd, J = 7.98, 0.90 Hz, 1H), 6.68 (dt, J
= 7.40, 1.10 Hz, 1H), 6.89 (d, J = 7.42 Hz, 1H), 7.03 (dt, J = 7.99, 1.43 Hz, 1H);
13
C
NMR δ 6.2, 28.0, 42.3, 70.3 (q, J
2
C-F = 27.50 Hz), 114.0, 117.9, 120.3, 125.6, 126.8 (q,
J
1
C-F = 289.3 Hz), 127.4, 141.0;
19
F NMR δ -80.38; HRMS (EI) m/z 230.1028,
calculated for C
11
H
13
F
3
N
2
230.1031.
2-Benzyl-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline (Table 5.4a, entry 3)
1
H NMR δ 3.09 (s, 2H), 3.79 (d, J = 16.71 Hz, 1H), 4.07 (d, J = 16.76 Hz, 1H), 6.57 (dd,
J = 7.99, 0.92 Hz, 1H), 6.67 (dt, J = 7.41, 1.12 Hz, 1H), 6.84 (dd, J = 7.46, 0.73 Hz, 1H),
7.03 (dt, J = 8.01, 1.41 Hz, 1H), 7.33-7.21 (m, 5H);
13
C NMR δ 40.9, 42.4, 70.16 (q, J
2
C-
F = 27.46 Hz), 114.4, 118.3, 120.0, 125.61, 125.72 (q, J
1
C-F = 289.42 Hz), 127.46,
127.71, 128.7, 130.9, 132.8, 140.6;
19
F NMR δ -79.74; HRMS (EI) m/z 292.1193,
calculated for C
16
H
15
F
3
N
2
292.1187.
2-(Difluoromethyl)-2-methyl-1,2,3,4-tetrahydroquinazoline (Table 5.4a, entry 4)
1
H NMR δ 1.34 (t, J = 1.69 Hz, 3H), 1.80 (brs, 1H), 3.85 (d, J = 16.86 Hz, 1H), 3.92 (d, J
= 16.86 Hz, 1H), 4.07 (brs, 1H), 5.64 (t, J = 56.30 Hz, 1H), 6.51 (dd, J = 8.00, 0.91 Hz,
1H), 6.68 (dt, J = 7.41, 1.13 Hz, 1H), 6.88 (dd, J = 7.46, 0.90 Hz, 1H), 7.02 (dt, J = 8.02,
1.52 Hz, 1H);
13
C NMR δ 20.4, 41.7, 67.1 (t, J
2
C-F = 21.9 Hz), 114.76, 115.1 (dd, J
1
C-F
= 249.80, 246.60 Hz), 117.9, 119.8, 125.8, 127.4, 141.0;
19
F NMR δ -131.33 (dd, J =
279.24 Hz, J = 56.46 Hz, 1F), -135.64 (dd, J = 277.71 Hz, J = 56.46 Hz, 1F); HRMS
(EI) m/z 198.0971, calculated for C
10
H
12
F
2
N
2
198.0969.
101
2-Methyl-2-(trifluoromethyl)-2,4-dihydro-1H-benzo[d][1,3]oxazine (Table 5.4a,
entry 5)
1
H NMR δ 1.62 (s, 3H), 4.30 (s, 1H), 4.84 (d, J = 14.43 Hz, 1H), 5.01 (d, J = 14.40 Hz,
1H), 6.70 (d, J = 8.01 Hz, 1H), 6.87 (t, J = 7.38 Hz, 1H), 6.99 (d, J = 7.50 Hz, 1H), 7.17
(t, J = 7.67 Hz, 1H);
13
C NMR δ 22.2, 63.8, 82.46 (q, J
2
C-F = 30.37 Hz), 115.1, 119.37,
119.68, 124.63 (q, J
1
C-F = 290.62 Hz), 124.64, 128.1, 138.7;
19
F NMR δ -81.56; HRMS
(EI) m/z 217.0715, calculated for C
10
H
10
F
3
NO 217.0714.
2-(Difluoromethyl)-2-methyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (Table 5.4a, entry
6)
1
H NMR δ 1.43 (t, 1.83 Hz, 3H), 4.18 (s, 1H), 4.79 (q, J = 14.80 Hz, 2H), 5.64 (dd, J =
56.57, 55.48 Hz, 1H), 6.60 (dd, J = 8.01, 0.70 Hz, 1H), 6.76 (dt, J = 7.44, 1.10 Hz, 1H),
6.89 (dd, J = 7.55, 0.88 Hz, 1H), 6.99-7.18 (m, 1H);
13
C NMR δ 18.8, 62.5, 82.4 (t, J
2
C-F
= 24.67 Hz), 113.9 (dd, J
1
C-F = 252.51, 246.44 Hz), 115.6, 119.08, 119.65, 124.7, 128.0,
139.2;
19
F NMR δ -132.32 (dd, J = 283.81 Hz, J = 56.46 Hz, 1F), -134.74 (dd, J = 283.81
Hz, J = 54.93 Hz, 1F); HRMS (EI) m/z 199.0812, calculated for C
10
H
11
F
2
NO 199.0809.
2-Ethyl-2-(trifluoromethyl)-2,4-dihydro-1H-benzo[d][1,3]oxazine (Table 5.4a, entry
7)
1
H NMR δ 0.96 (dd, J = 7.73, 7.20 Hz, 3H), 1.67-1.78 (m, 1H), 2.02-1.91 (m, 1H), 4.08
(s, 1H), 4.74 (d, J = 14.09 Hz, 1H), 4.95 (d, J = 14.21 Hz, 1H), 6.61 (d, J = 7.99 Hz, 1H),
6.76 (dt, J = 7.45, 1.05 Hz, 1H), 6.90 (d, J = 7.48 Hz, 1H), 7.08 (t, J = 7.68 Hz, 1H);
13
C
NMR δ 6.1, 28.3, 64.2, 84.1 (q, J
2
C-F = 28.91 Hz), 114.5, 119.00, 119.65, 124.6, 125.0
(q, J
1
C-F = 292.41 Hz), 128.1, 139.4;
19
F NMR δ -80.26; HRMS (EI) m/z 231.0878,
calculated for C
11
H
12
F
3
NO 231.0871.
102
2-Methyl-2-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (Table 5.4b, entry 1)
1
H NMR δ 1.68 (s, 3H), 6.42 (brs, 1H), 6.74 (dd, J = 13.42, 7.55 Hz, 2H), 7.27 (t, J =
7.04 Hz, 1H), 7.79 (d, J = 7.39 Hz, 1H), 8.21 (s, 1H);
13
C NMR δ 22.0, 68.8 (q, J
2
C-F =
30.34 Hz), 112,8, 113.2, 117.7, 124.8 (q, J
1
C-F = 293.82 Hz), 127.2, 133.6, 145.1, 163.8;
19
F NMR δ -85.33; HRMS (EI) m/z 230.0678, calculated for C
10
H
9
F
3
N
2
O 230.0667.
2-(Difluoromethyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one (Table 5.4b, entry 2)
1
H NMR δ 1.58 (d, J = 1.56 Hz, 3H), 5.79 (t, J = 56.41 Hz, 1H), 6.65 (d, J = 8.12 Hz,
1H), 6.77 (brs, 1H), 6.86 (t, J = 7.50 Hz, 1H), 7.26 (s, 1H), 7.33 (t, J = 7.32 Hz, 1H), 7.87
(d, J = 7.80 Hz, 1H);
13
C NMR δ 69.2 (t, J
2
C-F = 25.09 Hz), 113.9 (dd, J
1
C-F = 253.76,
251.40 Hz), 114.09, 114.32, 119.7, 128.6, 134.7, 144.7, 163.7;
19
F NMR δ -130.97 (dd, J
= 279.24 Hz, J = 56.46 Hz, 1F), -135.02 (dd, J = 279.24 Hz, J = 56.46 Hz, 1F); HRMS
(EI) m/z 212.0772, calculated for C
10
H
10
F
2
N
2
O 212.0761.
2-Ethyl-2-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (Table 5.4b, entry 3)
1
H NMR δ 1.14 (t, J = 7.41 Hz, 3H), 1.86 (m, 1H), 1.97 (m, 1H), 4.46 (brs, 1H), 6.67 (d,
J = 8.12 Hz, 1H), 6.84 (dt, J = 7.82, 0.96 Hz, 1H), 7.26 (s, 1H), 7.34 (ddd, J = 8.14, 7.33,
1.56 Hz, 1H), 7.87 (dd, J = 7.81, 1.42 Hz, 1H);
13
C NMR δ 6.8, 27.0, 72.79 (q, J
2
C-F =
29.71 Hz), 112.7, 113.7, 119.4, 125.09 (q, J
1
C-F = 293.28 Hz), 128.3, 134.8, 145.2,
164.8;
19
F NMR δ -85.45; HRMS (EI) m/z 244.0829, calculated for C
11
H
11
F
3
N
2
O
244.0823.
2-Benzyl-2-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (Table 5.4b, entry 4)
1
H NMR δ 3.18 (d, J = 14.47 Hz, 1H), 3.31 (d, J = 14.47 Hz, 1H), 4.62 (s, 1H), 6.63 (d, J
= 8.13 Hz, 1H), 6.79 (t, J = 7.55 Hz, 1H), 7.24-7.36 (m, 6H), 7.80 (d, J = 7.80 Hz, 1H),
8.12 (s, 1H);
13
C NMR δ 39.5, 72.46 (q, J
2
C-F = 29.12 Hz), 112.4, 113.5 118.2, 124.9 (q,
103
J
1
C-F = 294.44 Hz), 127.25, 127.54, 128.2, 131.0, 132.4, 134.0, 145.1, 164.1;
19
F NMR δ
- 83.95; HRMS (EI) m/z 306.0992, calculated for C
16
H
13
F
3
N
2
O 306.0980.
2-Methyl-2-(trifluoromethyl)-4H-benzo[d][1,3]oxathiin-4-one (Table 5.5, entry 1)
1
H NMR δ 1.96 (q, J = 1.01 Hz, 3H), 7.27 (dd, J = 7.78, 0.94 Hz, 1H), 7.33 (ddd, J =
7.68, 7.68, 1.17 Hz, 1H), 7.53 (ddd, J = 7.68, 7.68, 1.51 Hz, 1H), 8.18 (dd, J = 7.89, 1.48
Hz, 1H);
13
C NMR δ 23.0, 84.4 (q, J
2
C-F = 32.81 Hz), 121.8, 123.7 (q, J
1
C-F = 286.36
Hz), 126.6, 127.0, 132.2, 133.7, 134.5, 160.7;
19
F NMR δ -79.92; HRMS (EI) m/z
248.0132, calculated for C
10
H
7
F
3
O
2
S 248.0119.
2-Ethyl-2-(trifluoromethyl)-4H-benzo[d][1,3]oxathiin-4-one (Table 5.5, entry 2)
1
H NMR δ 1.22 (t, J = 7.52 Hz, 3H), 1.97-2.08 (m, 1H), 2.27-2.38 (m, 1H), 7.24-7.33 (m,
2H), 7.50 (dt, J = 7.78, 1.57 Hz, 1H), 8.17 (dd, J = 7.87, 1.52, Hz, 1H);
13
C NMR δ 7.8,
28.1, 87.7 (q, J
2
C-F = 31.14 Hz), 121.3, 124.0 (q, J
1
C-F = 287.31 Hz,) 126.6, 131.9,
133.9, 134.323, 160.7, 218.6;
19
F NMR δ -78.6; HRMS (FAB) m/z 263.0366, calculated
for C
11
H
9
F
3
O
2
S 263.0354.
2-Benzyl-2-(trifluoromethyl)-4H-benzo[d][1,3]oxathiin-4-one (Table 5.5, entry 3)
1
H NMR δ 3.19 (d, J = 14.64 Hz, 1H), 3.61 (d, J = 14.64 Hz, 1H), 7.04 (d, J = 7.91 Hz,
1H), 7.12 (dt, J = 7.71, 1.25 Hz, 1H), 7.24-7.37 (m, 6H), 8.00 (dd, J = 7.94, 1.52 Hz, 1H);
13
C NMR δ 40.7, 87.5 (q, J
2
C-F = 30.61 Hz,1C), 121.3, 123.9 (q, J
1
C-F = 287.94 Hz,),
124.7, 126.42, 126.63, 128.00, 128.33, 131.45, 131.91, 133.8, 134.3, 160.5;
19
F NMR δ
-78.12; HRMS (FAB) m/z 325.0526, calculated for C
16
H
11
F
3
O
2
S 325.0510.

104
2-Phenyl-2-(trifluoromethyl)-4H-benzo[d][1,3]oxathiin-4-one (Table 5.5, entry 4)
1
H NMR δ 7.18-7.23 (m, 1H), 7.30 (dd, J = 7.88, 1.19 Hz, 1H), 7.31-7.36 (m, 3H), 7.42
(dt, J = 7.44, 1.50 Hz, 1H), 7.73-7.77 (m, 2H), 8.04 (dd, J = 7.89, 1.47 Hz, 1H);
13
C NMR
δ 90.33 (q, J
2
C-F = 32.41 Hz), 122.34 (q, J
1
C-F = 284.95 Hz), 123.27, 127.41, 127.78,
127.85, 128.7, 130.5, 132.3, 133.35, 133.40, 134.7, 160.9;
19
F NMR δ -77.09; HRMS
(FAB) m/z 311.0339, calculated for C
15
H
9
F
3
O
2
S 311.0354.
2-(Difluoromethyl)-2-methyl-4H-benzo[d][1,3]oxathiin-4-one (Table 5.5, entry 5)
1
H NMR δ 1.85 (t, J = 1.53 Hz, 3H), 5.87 (dd, J = 56.04, 54.89 Hz, 1H), 7.28-7.36 (m,
2H), 7.53 (dt, J = 7.49, 1.51 Hz, 1H), 8.18 (dd, J = 7.94, 1.53 Hz, 1H);
13
C NMR δ 21.0,
85.4 (t, J
2
C-F = 25.0 Hz), 113.07 (dd, J
1
C-F = 254.37, 250.97 Hz), 122.6, 127.00, 127.39,
132.3, 134.22, 134.49, 161.3;
19
F NMR δ -125.10 (dd, J = 280.76 Hz, J = 54.93 Hz, 1F),
-130.06 (dd, J = 282.29 Hz, J = 56.46 Hz, 1F); HRMS (EI) m/z 230.0212, calculated for
C
10
H
8
F
2
O
2
S 230.0213.

105
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50. Conrow, R. E. Org. Lett. 2006, 8, 2441.
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2006, 3638.

52. Anzalone, P. W.; Mohan, R. S. Synthesis 2005, 2661.
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54. Dziedzic, M.; Lipner, G.; Furman, B. Tetrahedron Lett. 2005, 46, 6861.
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56. Shi, M.; Yang, Y-H.; Xu, B. Tetrahedron 2005, 61, 1893.
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110
6 Chapter 6: Cyclodehydration of Fluorinated Diols Using
the Mitsunobu Reaction: Highly Efficient Synthesis of
Trifluoromethylated Cyclic Ethers

6.1 Chapter 6: Introduction

Fluorinated ethers emerge as highly promising substitutes for
chlorofluorohydrocarbons (CFCs) owing to their excellent solvent properties, zero ozone
depleting potential, and low toxicity.
1-2
They have been widely used as detergents,
solvents, lubricants, heat transfer media etc.
3-4
Aromatic fluoromethylated ethers are
known to have significant applications in the pharmaceutical and agricultural arenas.
5-6

Albeit the methods known for the synthesis of these compounds using reagents such as
SF
4
7
or CCl
4
/HF,
8-10
simple and convenient protocols are rare. Developments during this
decade in this area include synthesis of trifluoromethyl ethers via xanthates utilizing
BrF
3
,
11
trapping of CF
3
OH as useful ether derivatives,
12
alkylation of fluorinated
alkoxides generated from the corresponding fluorinated acyl halides,
13
electrophilic
fluoromethylation of alcohols,
14-18
and trifluoromethoxylation using trifluoromethyl
triflate.
19
Fluorinated cyclic ethers have received a lot of attention in synthetic organic
chemistry due to their wide variety of applications such as blood substitutes, various
effective drug candidates
20
and anesthetics.
21
Despite their unique bioactivity and high
demand, the synthesis of fluorinated cyclic ethers is still not extensively investigated.
22
There have been a few synthetic methods for the preparation of fluorinated cyclic ethers,
including alkoxide alkylations (Williamson ether synthesis),
23
intramolecular cyclization
of fluoromethylated alkenols
24
and the cyclization of the corresponding fluorinated
alcohols mediated by strong acids.
25
Quite often, these synthetic routes can lead to
111
undesired by-products and low selectivity caused by the harsh reaction conditions
involved. On the other hand, the Mitsunobu reaction is known to permit the formation of
C-C, C-O, C-N and C-S bonds with primary or secondary alcohols under mild
conditions.
26
In particular, Falck and coworkers have achieved the intermolecular
condensation of polyfluorinated alcohols to the corresponding ethers under the
Mitsunobu conditions.
27
Although the preparation of fluorinated cyclic ethers via the
Mitsunobu reaction has been mentioned in the patent literature,
28-29
the synthetic and
mechanistic aspects of this methodology have not been studied in detail.
Many fluororganics have unique physical properties suitable for their application
as pharmaceuticals, agrochemicals, and organic materials.
30-32
It is well-known that
presence of fluorine can result in substantial changes in the biological properties of an
organic compound.
30-37
Incorporation of fluorine in drug molecules can affect their
physicochemical properties, such as bond strength, liophilicity, bioavailability,
conformation, electrostatic potential, dipole moment, pKa, etc.; pharmacokinetic
properties, such as tissue distribution; rate of metabolism; or pharmacological
consequences, such as pharmacodynamics and toxicology. In many instances, fluorine is
introduced as fluoromethyl groups (CF
3
, CF
2
H, CH
2
F etc.) and effective reagents and
methods have been developed during the last two decades. Nucleophilic
trifluoromethylation using Ruppert-Prakash reagent
38
and electrophilic
trfluoromethylation using Umemoto’s reagent
39
are two key methods widely used for the
introduction of trifluoromethyl groups into organic substrates. Antidepressant behavior of
various basic derivatives of phthalans and chromans has been studied followed by
investigations of pharmacological consequence of phthalan ring oxygen in the
112
development of conformationally defined adrenergic agents.
23,40-42
Since the
incorporation of CF
3
groups into drug candidates often improves their binding selectivity,
lipophilicity, and metabolic stability,
43-46
similar approach in the case of cyclic ethers
such as oxiranes, phthalans and their homologues are highly warranted. Therefore, we
have focused on the development of a simple and efficient protocol for the synthesis of
fluorinated cyclic ethers.

6.2 Chapter 6: Results and Discussion

Herein, we would like to disclose the synthesis of trifluoromethylated cyclic
ethers via the Mitsunobu cyclodehydration of fluorinated diols with high efficiency and
excellent stereoselectivity (Scheme 6.1).
OH
OH
O
n
R
1
R
2 R
1
R
2
n
Bu
3
P/TMAD
Benzene
r.t., 12 hr
n = 1, 2, 3
R
1
=R
2
=CF
3
R
1
=CF
3
, R
2
=H
R
1
=CF
3
, R
2
=CH
3
TMAD =
N
N
O
NMe
2
O
Me
2
N
1
2

Scheme 6.1 Synthesis of trifluoromethylated cyclic ethers via the Mitsunobu
cyclodehydration

Owing to mild reaction conditions, high stereospecificity, and versatility, the
Mitsunobu reaction
47-51
has been widely used in organic synthesis. Significant progress
has been made in recent years in the reagent modification and in the application of the
Mitsunobu reaction
52-55
in many useful synthetic protocols. A useful strategy involving
the Mitsunobu reaction for the cyclodehydration of fluorinated diols under mild
conditions in the absence of acids was our main goal.
113
Table 6.1 Optimization of the Mitsunobu Cyclodehydration Reaction

OH
OH
CF
3
O
CF
3
Entry
Azodicarbonyl
reagent
Phosphine
reagent
yield (%)
a
1
2
3
4
5
6
PPh
3
DEAD
PBu
3
DIAD 0
PBu
3
ADDP 69
PMe
3
ADDP 32
TMAD PBu
3
89
TMAD PPh
3
7
69
e
55
37
-
DIAD PPh
3
39
8
DEAD PPh
3 61
b
ADDP PBu
3 47
c
DCM
DCM
ADDP Benzene 75
DCM
Benzene
THF
ADDP PBu
3
71 Et
2
O
DCM
PBu
3
TMAD PMe
3
THF
55
d
Benzene
Benzene
Benzene
Benzene
Solvent
9
10
11
12
CMBP 13
a
All reactions were performed in accordance with the general procedure in the
experimental section unless stated otherwise.
b,c 19
F NMR conversion.
d
Reaction
carried out at 60
o
C.
e
Reaction carried out at 100
o
C.
1d 2d
Reagents
Solvent

114
Initial attempts to synthesize the fluorinated cyclic ethers under the usual
Mitsunobu conditions resulted in products with low yield (Table 6.1, entry 1). In order to
enhance the efficacy of the reaction, various modifications of the reaction parameters
have been carried out. With the generally used azodicarboxylate reagents such as
diisopropyl azodicarboxylate (DIAD) and diethyl azodicarboxylate (DEAD) at room
temperature, products were formed in 37-39% yield range (Table 6.1, entries 1-3).
Although a moderate yield was observed by increasing the temperature to 100
0
C. (Table
6.1, entry 13), the yield could not be further improved even after multiple attempts with
modification of reaction parameters including the addition sequence of reagents,
changing the quantity and proportion of substrates and the reagents as well as the reaction
media.
Based on the studies reported by Falck,
27
we employed the 1,1’-
(azodicarbonyl)dipiperidine (ADDP)-tributyl-phosphine (TBP) system, which has been
shown to be superior to the traditional DEAD-TPP and DIAD-TPP systems for less
acidic nucleophiles (pK
a
≈ 11-12).
56
Although the combination of ADDP with PMe
3
gave
only 32% yield (Table 6.1, entry 5), we were delighted to find that the ADDP/TBP
system led to an increase in yield to 75% when the reaction was carried out in anhydrous
benzene (Table 6.1, entry 6-9). Therefore, it is reasonable to conclude that the relatively
low acidity of the substrates suppress the rate of the reaction and higher acidity results in
higher yields.
Both N,N,N’,N’-tetramethylazodicarboxamides (TMAD) and cyanomethylene-
tributylphosphorane (CMBP) are known to mediate the Mitsunobu reaction with
nucleophiles having pK
a
values higher than 13.
28
We observed that both the TMAD-Bu
3
P
115
and CMBP systems were significantly better than the ADDP-TBP or the traditional
DIAD/DEAD-TPP systems. While it has been shown that CMBP is a much more reactive
reagent toward less acidic substrates in comparison with TMAD-TBP,
57
we have
discovered that the TMAD-TBP system afforded a considerably better yield than the
CMBP system suggesting that additional factors other than the pK
a
values of the
nucleophiles influence the yields (Table 6.1, entries 10 and 13). Due to the low stability
and the difficulty in practical application of CMBP, the TMAD-TBP system has been
preferentially utilized for further optimization. The optimal conditions were eventually
found to employ 2.0 equivalent of Bu
3
P and 2.3 equiv of TMAD using benzene as the
solvent (Table 6.1, entry 10). This reaction conditions not only achieve quantitative
conversion of the diol (monitored by
19
F NMR) but also allows for the easy separation of
the product from the byproducts.
After optimizing the reaction conditions, we have investigated the scope of this
protocol to various substrates with different acidities and steric demands. The
methodology is found to be widely applicable to the synthesis of cyclic ethers with 3-7
membered ring size (Table 6.2). It is worth mentioning that the cyclic ethers with
considerable ring strain can also be achieved in moderate yields by this protocol (Table
6.2, entries a-c). For relatively larger ring system, the yields are independent of the ring
size. The methodology is suitable for both primary and secondary alcohols as well as
benzylic and aliphatic alcohols as electrophiles to afford the corresponding products in
moderate to good yields. Reactions involving secondary alcohols as electrophiles (Table
6.2, entries a-c) results in lower yields than the primary alcohol counterparts, primarily
due to steric reasons. Also, the steric nature of the nucleophilic hydroxyl groups
116
significantly affects the reaction yields. As the steric bulkiness increases, the yield
decreases (Table 6.2, entries b-f and h-j). However, the “unexpected” high yield
observed in the case of substrate in entry k can be attributed to the anisotropic steric
effect of the phenyl group. A series of trifluoromethyl and bis(trfluoromethyl) substituted
cyclic ethers were prepared in moderate to high yields. A diol bearing the difluoromethyl
phenyl sulfone functionality also underwent the cyclodehydration reaction to generate the
corresponding product in almost quantitative yield. (Table 6.2, entry g).
117
Table 6.2 The Mitsunobu Cyclodehydration of Fluorinated Diols
a
Isolated yields.
b
Determined by 2D NMR.
c
Isolated yield of an inseparable
mixture of diastereoisomers. Determined by
19
F NMR analysis of the crude
mixture.
Entry Cyclic ether 2 Diol 1 Yield (%)
a
O
F
3
C
CH
3
O
CF
3
O
CH
3 F
3
C
O
F
3
C CF
3
O
CF
3
O
Ph CF
3
O
F
3
C
CF
3
d
e
f
h
i
j
k
l
g
OH
OH
F
3
C
CH
3
OH
OH
F
3
C
CF
3
OH
OH
CF 3
OH
OH
F
3
C
CH
3
OH
OH
F
3
C CF
3
OH
OH
CF
3
OH
OH
Ph
CF
3
78
90
67
89
66
38
40
OH
F
3
C
OH
CH
3
O
F
3
C
CH
3
80
O
CF
2
SO
2
Ph
OH
OH
CF
2
SO
2
Ph
99
b
a
O
Ph
CF
3
Ph
H
68
b
Ph
O
CF
3
Ph CF
3
OH OH
60
c
Ph
HO OH
CF
3
Ph H
c
Ph
O
CF
3
Ph
CF
3
OH OH
56
CF 3
CF
3

118
The present methodology has also indicated excellent stereoselectivity. This has
been investigated by studying the cyclodehydration of the diastereoisomerically pure
trifluoromethyl aryl substituted diol 1a (Scheme 6.2). The relative configuration of 1a
has been determined by
1
H NOESY and
1
H-
19
F HOESY spectral studies. The presence of
a strong
1
H-
1
H nOe between the two hydroxyl groups but undetectable
1
H-
1
H nOe
between the two phenyl groups suggests the gauche conformation of the OH groups and
the anti position of the two phenyl rings. The
1
H-
19
F HOESY further confirms the result
derived from the
1
H-
1
H nOe due to the strong
1
H-
19
F interaction between the F in CF
3

group and the proton in Ph’ group (Figure 6.1). In fact, we found that Mitsunobu
cyclodehyration reaction of 1a afforded the corresponding oxirane in moderate yield
(68%) with quantitative inversion of configuration (100% dr) as anticipated (Table 6.2,
entries a-c).

CF
3
Ph OH
OH
Ph' H
nOe
No nOe
1
H NOESY
CF
3
Ph OH
OH
Ph' H
1
H-
19
F HOESY
Weak nOe
OH OH
H
Ph' CF
3
Ph
The Ph groups are in
trans position.
1a 1a 1a

Figure 6.1 The NMR analysis of 3,3,3-trifluoro-1,2-diphenylpropane-1,2-diol (1a)

Beside the development of the synthetic route into a practically useful
methodology, we have also investigated the mechanistic aspects of the reaction. As
reported by Verdaguer et al.,
58
the use of PBu
3
under the Mitsunobu cyclodehydration
can lead to an inversion of configuration of the diols, whereas the application of PPh
3

119
results in the retention of relative configuration. Although the similar inversion result was
observed in the PBu
3
-mediated cyclodehydration of 1a, the reported retention of
configuration was not found when PPh
3
was used. Differing from Verdaguer’s findings,
this result evidently suggests that the diastereoselectivity in the Mitsunobu
cyclodehydration reaction of fluorinated diol is independent of the steric demands and
electronegativity of the phosphines. Consequently, the traditional Mitsunobu mechanism
involving the formation of the pentacoordinate phosphorane 3 arising from MBH betaine
intermediates can be proposed to rationalize the observations (Scheme 6.2, A and B). It is
apparent that a high diastereoselectivity can be achieved in the pathway A no matter
whether 4a or 4b are formed.
58
According to Richard,
59
the transition states involving the
intermediates 4c and 4d are expected to be unfavorable due to their thermodynamic
instability and kinetic stability. In other words, the intermediates 4e and 4f can play a
significant role in the diastereoselectivity of the reaction. If reaction follows the pathway
B at any appreciable rate, a mixture with lower diastereoisomeric purity is likely to be
formed. Since quantitative inversion of configuration was observed in the product, the
pathway A is obviously preferred. More electron deficient and steric demanding PPh
3

was found to have no effect on the stereospecificity suggesting that the Mitsunobu
cyclodehydration reaction may be phosphine independent. However, further investigation
is still needed.
120
O
O
P
Ph
O
-
O P
+
-
O
O P
+
Ph
HO OH
CF
3
Ph H
CF
3
Ph
H
Ph
H
O
Ph
CF
3
Ph
H
Ph
CF
3
CF
3
Ph
Ph
H
Ph
CF
3
Ph
H
-
O
Ph
Ph
CF
3
H
-
O
1a
O
CF
3
Ph
Ph
H
2a
2a'
4d 4c
3
4a
4b
O
Ph
CF
3
Ph
H
2a
A
B
+
inversion
+
inversion retention
- Ph
3
P=O
Ph
Ph
CF
3
H
4e
4f
+
inversion retention
O
-
Ph
Ph
CF
3
H
+
O
-
+
+
inversion
+
retention
+

Scheme 6.2 Proposed reaction pathway

6.3 Chapter 6: Conclusion

In summary, a highly efficient Mitsunobu protocol for the stereoselective
cyclodehydration of fluorinated diols to fluorinated cyclic ethers has been developed.
This methodology has been found to be widely applicable for the synthesis of a series of
fluorinated cyclic ethers of varying ring size (n = 3-7) in moderate to high yields as well
as in high diastereoselectivity.

6.4 Chapter 6: Experimental

6.4.1 General
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. TMAD
60
, trifluoroacetaldehyde
61
and 3-(2-bromophenyl)propan-1-ol
62-63
were
prepared according to known procedures. The DriSolv
®
solvents were purchased from
EMD
TM
and used without further purification. Products were separated and purified by
121
column chromatography (silica gel, 60-200 mesh from silicycle).
1
H,
13
C,
19
F and 2D
spectra including COSY and NOESY were recorded on 400 MHz Varian NMR
spectrometer. The HOESY spectra was recorded on 500 MHz Bruker NMR spectrometer.
1
H NMR chemical shifts were determined relative to tetramethylsilane (TMS) at  0.0
ppm or to residual solvent peak (at δ 7.26 ppm for CDCl
3
, and  3.31 ppm for CD
3
OD).
13
C NMR shifts were determined relative to TMS at δ 0.00 ppm or to the residual solvent
peak (at  77.16 ppm for CDCl
3
at and  49.00 ppm for CD
3
OD).
19
F NMR chemical
shifts were determined relative to internal standard CFCl
3
at δ 0.00 ppm. Mass spectra
were recorded on a high resolution mass spectrometer, in the EI, FAB or ESI mode.

6.4.2 Preparation of cis-3,3,3-Trifluoro-1,2-diphenylpopane-1,2-diol (1a)

cis-3,3,3-Trifluoro-1,2-diphenylpropane-1,2-diol (1a) was prepared according to
the known procedure (Scheme 6.3).
64
Addition of of TMSCF
3
(1.2 equivalent) to benzyl
(1 equivalent) gave the corresponding monosilyl-protected ether intermediate, which on
hydrolysis using TBAF produced the diphenyl keto alcohol in 83% yield (R
f
= 0.73, 10:1
mixture of hexane and ethylacetate).
65
The corresponding fluorinated diol 1a was
obtained by reduction of the diphenyl keto alcohol using sodium borohydride (yield 86%,
R
f
= 0.43, 4:1 mixture of hexane and ethylacetate).
Ph
Ph
O
O
TMSCF
3
Ph
Ph
O
TMSO CF
3
TBAF/H
2
O
Ph
Ph
O
HO CF
3
NaBH
4
Ph
HO OH
CF
3
Ph H
1a

Scheme 6.3 Preparation of cis-3,3,3-Trifluoro-1,2-diphenylpopane-1,2-diol

122
6.4.3 Typical Procedure for the Preparation of Fluorinated Diols 1d-f and 1h-l
(Table 6.2, Entries d-f, h-l); 1,1,1-Trifluoro-2-[2-
(hydroxymethyl)phenyl]propan-2-ol (1e)

Triisopropylsilyl-protected alcohol was prepared following a reported procedure
(Scheme 6.4).
66
To a stirred solution of 2-iodobenzyl alcohol (1.84 g, 7.85 mmol) in THF
(22 mL) was added imidazole (1.6 g, 22.55 mmol) and stirred for 15 min.
Triisopropylsilyl chloride (TIPSCl, 1.84 g, 10.21 mmol) was then added to the solution
and allowed to stir for another 12 h at room temperature. The reaction mixture was
quenched with water (30 mL) and extracted CH
2
Cl
2
(3 x 15 mL). The combined organic
layers were washed with brine, dried over MgSO
4
, filtered and evaporated under reduced
pressure. The crude (2-iodobenzyloxy)triisopropylsilane obtained was dried and used as
is in the next step. To a stirred solution of (2-iodobenzyloxy)triisopropylsilane (1.40 g,
3.59 mmol) in anhydrous Et
2
O (23.5 mL) was added solution of 1.7 M t-BuLi in pentane
(4.22 mL, 7.18 mmol) dropwise at -78
o
C under argon. After the mixture was stirred for
10 min 1,1,1-trifluoroacetone (0.804 g, 7.18 mmol) was added. When the reaction
mixture turned pale yellow, it was warmed to room temperature and was quenched with
1M HCl (40 mL). The reaction mixture was extracted with ether (3 x 15 mL), dried over
MgSO
4
, filtered and evaporated under reduced pressure. The crude reaction mixture was
purified by flash chromatography to obtain 1,1,1-trifluoro-2-(2-
(triisopropylsilyloxymethyl)phenyl)-propan-2-ol. 1,1,1-Trifluoro-2-(2-
((triisopropylsilyloxy)methyl)phenyl)propan-2-ol (771 mg, 2.05 mmol) was suspended in
THF (4 mL) and cooled to 0 °C. A 1.0 M solution of TBAF (2.67 mL, 2.67 mmol, 1.3
equiv) was added and stirred for 1 h and the THF was removed by vacuum evaporation.
123
The residual oil was immediately purified by chromatography on silica gel (1:1 mixture
of hexane and ethyl acetate as eluent) to give the corresponding diol in 62% yield.

OTIPS
I
OTIPS
CH
3
F
3
C
OH
OH
CH
3
F
3
C
OH
OH
I
TIPSCl
Imidazole
n-BuLi
F
3
C
H
3
C
O
1M HCl
TBAF/H
2
O
1e

Scheme 6.4 Typical Procedure for the Preparation of Fluorinated Diols 1d-f and 1h-l

6.4.4 General Procedure for the Preparation of 1b and 1c
4,4,4-Trifluoro-3-hydroxy-1-phenylbutan-1-one was prepared according to the
literature procedure (Scheme 6.5).
67
The subsequent aldol product or the commercially
available 4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyrophenone was then subjected
to reduction
68
using sodium borohydride to give the corresponding diol.

Ph
R
OH OH
CF
3
1b: R = H, 1c: R = CF
3
Ph
R
O OH
CF
3
NaBH
4

Scheme 6.5 General Procedure for compound 1b and 1c

6.4.5 General Procedure for the Preparation of 1g and 1h
2-(Triisopropylsilyloxymethyl)benzaldehyde was prepared from o-xylene glycol
following the known procedure (Scheme 6.6).
65
The aldehyde could either undergo
trifluoromethylation with TMSCF
3
38
or difluoromethylation with difluoromethyl phenyl
sulfone
69
to give the corresponding protected fluorinated alcohols. Removal of the
protecting groups with TBAF gives the desired fluorinated diols.

124
OTIPS
H
O
(1) TMSCF
3
or PhSO
2
CF
2
H
(2) TBAF
OH
R
OH
1g: R = CF
3
, 1h: PhSO
2
CF
2

Scheme 6.6 General Procedure for compound 1g and 1h

6.4.6 Typical Experimental Procedure for the Mitsunobu Cyclodehydration
Reaction

To a stirred solution of fluorinated diol (49.4 mg, 0.24 mmol) in anhydrous
benzene (2.5 mL) was added tributylphosphine (0.12 mL, 0.48 mmol) followed by
TMAD (95 mg, 0.55 mmol) at room temperature. The reaction mixture was then flushed
with argon, sealed and allowed to stir for 12 h at the same temperature. The crude
reaction mixture was then purified by flash column chromatography (silica gel 60-230
mesh, 10:1 mixture of pentane and CH
2
Cl
2
as eluent) to give the cyclic ether (40 mg,
89%) as a colorless liquid.
6.4.7 Spectral Data

(1R,2R) and (1S, 2S)-3,3,3-Trifluoro-1,2-diphenylpropane-1,2-diol (1a)
1
H NMR:  7.71-7.66 (m, 2H), 7.49-7.40 (m, 3H), 7.40-7.31 (m, 5H), 5.34 (d, J = 3.6 Hz,
1H), 3.05 (s, 1H), 2.14 (d, J = 3.7 Hz, 1H);
13
C NMR:  137.06, 135.26, 129.04, 128.96,
128.54, 128.33, 127.86, 126.53, 124.67 (q,
1
J
C-F
= 286.3Hz), 79.53 (q,
2
J
C-F
= 26.8 Hz),
75.93;
19
F NMR:      HRMS (EI): m/z [M-H
2
O]
+
found 264.0762, calculated for
C
15
H
11
OF
3
    
125
4,4,4-Trifluoro-1-phenylbutane-1,3-diol (1b) 
1
H NMR:  7.43-7.28 (m, 10H), 5.11 (dd, J = 2.8 Hz, J = 8.8 Hz, 1H), 4.99 (dd, J = 3.5
Hz, J = 9.7 Hz, 1H), 4.36-4.16 (m, 2H), 4.05 (bs, 1H), 3.48 (bs, 1H), 2.79 (bs, 1H), 2.46
(bs, 1H), 2.20-1.96 (m, 4H);
13
C NMR:  143.09, 142.84, 128.85, 128.77, 128.45, 128.09,
125.65, 125.46, 125.17 (q,
1
J
C-F
= 287.1 Hz), 124.47 (q,
1
J
C-F
= 280.9 Hz), 74.12, 70.69,
70.63 (q,
2
J
C-F
= 31.6 Hz), 67.88 (q,
2
J
C-F
= 31.3 Hz), 37.64, 37.47;
19
F NMR:  -79.89 (d,
J = 7.0 Hz, 3F) 62%, -80.84 (d, J = 6.5Hz, 3F).

4,4,4-Trifluoro-1-phenyl-3-(trifluoromethyl)butane-1,3-diol (1c)
1
H NMR:  7.50-7.38 (m, 5H), 6.38 (s, 1H), 5.31 (d, J = 11.6 Hz, 1H), 2.88 (s, 1H), 2.41
(dddd, J = 1.9 Hz, J = 3.9 Hz, J = 11.6 Hz, J = 15.5 Hz, 1H), 2.24 (d, J = 15.3 Hz, 1H);
13
C NMR:  141.99, 129.02, 125.42, 123.46 (q,
1
J
C-F
= 287.9 Hz), 122.59 (q,
1
J
C-F
=
287.2 Hz), 76.44 (septet,
2
J
C-F
= 29.4 Hz), 71.87, 36.25;
19
F NMR:  -75.88 (q, J = 10.0
Hz, 3F), -79.82 (q, J = 9.8 Hz, 3F).

2,2,2-Trifluoro-1-(2-(hydroxymethyl)phenyl)ethanol (1d)
1
H NMR:  7.63-7.57 (m, 1H), 7.44-7.34 (m, 3H), 5.43 (q, J = 7.1 Hz, 1H), 4.84-4.76 (m,
2H), 3.80 (bs, 1H), 2.21 (bs, 1H);
13
C NMR:  138.49, 133.32, 129.95, 129.71, 128.92,
128.82, 124.63 (q,
1
J
C-F
= 282.6 Hz), 70.41 (q,
2
J
C-F
= 32.2 Hz), 64.09;
19
F NMR:  -
77.37 (d, J = 5.6 Hz, 3F).

126
1,1,1-Trifluoro-2-(2-(hydroxymethyl)phenyl)propan-2-ol (1e)
1
H NMR (CD
3
OD):  7.52-7.49 (m, 1H), 7.39-7.35 (m, 1H), 7.29 (dt, J = 1.5 Hz, J = 7.5
Hz, 1H), 7.25-7.20 (m, 1H), 4.97 (d, J = 13.6 Hz, 1H), 4.77 (d, J =13.6 Hz, 1H 8 Hz),
13
C NMR (CD
3
OD): 142.29, 137.89, 130.86, 129.58, 129.37, (q,
3
J = 1.7 Hz), 128.13,
127.71 (q,
1
J = 285.9 Hz), 77.94 (q,
2
J = 28.6 Hz), 64.77, 25.10 (q,
3
J = 1.3 Hz);
19
F
NMR:  -81.61.

1,1,1,3,3,3-Hexafluoro-2-(2-(hydroxymethyl)phenyl)propan-2-ol (1f)
1
H NMR:  7.81-7.74 (m, 1H), 7.66 (bs, 1H), 7.49-7.41 (m, 2H), 7.39-7.32 (m, 2H), 4.95
(s, 1H), 2.79 (bs, 1H);
13
C NMR  138.16, 132.67, 130.27, 130.11, 129.28 (heptet,
3
J =
3.4 Hz), 129.22, 122.88 (q,
1
J
C-F
= 288.9 Hz), 104.99, 79.75 (heptet,
2
J = 29.4 Hz), 66.67;
19
F NMR:  -75.46.

2,2-Difluoro-1-(2-(hydroxymethyl)phenyl)-2-(phenylsulfonyl)-ethanol (1g)
1
H NMR:  8.01 (d, 7.5 Hz, 2H), 7.80-7.74 (m, 1H), 7.66-7.58 (m, 3H), 7.40-7.32 (m,
3H), 6.02 (dd, J = 2.4 Hz, J = 22.1 Hz, 1H), 4.76 (s, 2H), 3.93 (bs, 1H), 2.18 (bs, 1H);
13
C
NMR:  138.90, 135.59, 132.56, 132.45, 130.70, 129.67, 129.52, 129.34, 129.26, 128.45,
120.64 (dd,
1
J
C-F
= 289.0 Hz,
1
J
C-F
= 299.5 Hz), 67.97 (dd,
2
J
C-F
= 19.2 Hz,
2
J
C-F
= 26.5
Hz), 63.55;
19
F NMR:  -104.25 (dd, J = 2.0 Hz, J = 238.0 Hz, 1F), -118.41 (dd, J = 22.1
Hz, J = 238.0 Hz, 1F).

127
2,2,2-Trifluoro-1-(2-(2-hydroxyethyl)phenyl)ethanol (1h)
1
H NMR:  7.54 (d, J = 7.6 Hz, 1H), 7.28-7.16 (m, 3H), 5.32 (q, J = 7.0 Hz, 1H), 3.66 (t,
J = 7.3 Hz, 2H), 2.92 (td, J = 7.3 Hz, J = 14.6 Hz, 1H), 2.79 (td, J=7.9Hz, J=22.6Hz, 1H);
13
C NMR:  137.28, 133.95, 129.85, 128.52, 127.64 (q,
3
J = 1.3 Hz), 126.14, 125.14 (q,
1
J
C-F
= 282 Hz), 67.73 (q,
2
J
C-F
= 31.2 Hz), 62.43, 35.30;
19
F NMR:   -74.89 (dd, J = 2.5
Hz, J = 6.6 Hz, 3F).

1,1,1-Trifluoro-2-(2-(2-hydroxyethyl)phenyl)propan-2-ol (1i)
1
H NMR:  7.41 (d, J=7.9Hz, 1H), 7.35-7.30 (m, 1H), 7.26-7.21 (m, 2H), 5.49 (bs, 1H),
4.03 (td, J = 4.6 Hz, J = 9.4 Hz, 1H), 3.86 (dt, J = 3.5 Hz, J = 9.6 Hz, 1H), 3.70 (ddd, J =
4.7 Hz, J = 9.7 Hz, J = 14.2 Hz, 1H), 2.96 (td, J = 4.2 Hz, J = 13.9 Hz, 1H), 2.13 (bs,
1H), 1.82-1.80 (m, 3H);
13
C NMR:  138.88, 137.94, 132.33, 128.97, 128.29, 126.39,
125.93 (q,
1
J
C-F
= 285.9 Hz), 77.20 (q, J = 9.7 Hz), 64.34, 35.83, 26.12;
19
F NMR: 
   

1,1,1,3,3,3-Hexafluoro-2-(2-(2-hydroxyethyl)phenyl)propan-2-ol (1j)
1
H NMR:  7.68 (d, J = 8.2 Hz, 1H), 7.43 (dt, J =1.3 Hz, J = 7.5 Hz, 1H), 7.34-7.27 (m,
2H), 4.01 (t, J = 5.6 Hz, 2H), 3.36 (t, J = 5.6 Hz, 2H), 2.22 (bs, 1H);
13
C NMR:  139.79,
133.15, 130.38, 130.27, 128.16, 126.73, 123.13 (q,
1
J
C-F
= 288.6 Hz), 79.92 (quintet,
2
J
C-F

=29.3 Hz), 64.08, 35.44;
19
F NMR:  -74.81.


128
2,2,2-Trifluoro-1-(2-(2-hydroxyethyl)phenyl)-1-phenylethanol (1k)
1
H NMR:  7.76 (d, J = 8.0 Hz, 1H), 7.47-7.40 (m, 3H), 7.40-7.26 (m, 5H), 5.87 (bs, 1H),
4.00-3.63 (m, 2H), 2.97-2.86 (m, 1H), 2.46-2.35 (m, 1H), 1.96 (bs, 1H);
13
C NMR: 
140.72, 138.88, 138.81, 132.21, 129.13, 128.17, 127.80, 127.77, 127.42 (q,
3
J
C-F
= 3.8
Hz), 126.02, 125.19 (q,
1
J
C-F
= 286.5 Hz), 79.85 (q,
2
J
C-F
= 27.2 Hz), 64.11, 34.84;
19
F
NMR:  -74.53. 

3-(2-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)phenyl)propan-1-ol (1l)
1
H NMR:  7.36-7.30 (m, 1H), 7.27-7.18 (m, 2H), 7.18-7.12 (m, 1H), 5.21 (s, 1H), 3.60-
3.51 (m, 1H), 3.50-3.45 (m, 1H), 3.45-3.33 (m, 1H), 3.12 (s, 1H), 2.87-2.78 (m, 1H),
1.93-1.81 (m, 2H), 1.77 (s, 3H);
19
F NMR:      

(2S,3R)-2,3-Diphenyl-2-(trifluoromethyl)oxirane (2a)
70
1
H NMR:  7.32-7.20 (m, 5H), 7.19-7.10 (m, 3H), 7.02-6.96 (m, 2H), 4.61 (s, 1H);
13
C
NMR:  131.96, 129.28, 129.21, 128.50, 128.12, 128.08, 127.93, 126.70, 123.11 (q,
1
J
C-F

= 279.5 Hz), 64.58 (q,
2
J
C-F
= 35.7 Hz), 60.43;
19
F NMR:       

2-Phenyl-4-(trifluoromethyl)oxetane (2b)
1
H NMR:  7.31-7.48 (m, 10H), 5.87 (t, 7.54 Hz, 1H), 5.80 (t, J = 7.7 Hz, 1H), 4.98-5.08
(m, 1H), 4.85-4.96 (m, 1H), 3.04-3.14 (m, 2H), 2.75-2.91 (m, 2H);
13
C NMR:  141.53,
140.76, 128.72, 128.60, 128.57, 128.53, 125.54, 125.25, 124.93 (q,
1
J
C-F
= 280.2 Hz),
123.77 (q,
1
J
C-F
= 279 Hz), 81.90, 79.89, 74.14 (q,
2
J
C-F
= 35.2 Hz), 72.72 (q,
2
J
C-F
= 36.1
129
Hz), 30.15, 30.08;
19
F NMR:          HRMS (EI): m/z 202.0599, calculated for
C
10
H
9
OF
3
    

4-Phenyl-2,2-bis(trifluoromethyl)oxetane (2c)
1
H NMR:  7.44-7.34 (m, 5H), 5.92 (t, 7.68 Hz, 1H), 3.23-3.19 (m, 1H), 3.12-3.04 (m,
1H);
13
C NMR:  138.94, 129.08, 128.81, 125.40, 123.02 (q,
1
J
C-F
= 284.6 Hz), 121.65
(q,
1
J
C-F
= 283.0 Hz), 80.17, 78.57 (quintet,
2
J
C-F
= 33.3 Hz), 31.21;
19
F NMR  -78.68 (q,
J = 8.9 Hz, 3F), -79.53 (q, J = 8.9Hz, 3F)  HRMS (EI): m/z 270.0482, calculated for
C
11
H
8
OF
6
    

1-(Trifluoromethyl)-1,3-dihydroisobenzofuran (2d)
1
H NMR:  7.44-7.38 (m, 2H), 7.38-7.32 (m, 1H), 7.32-7.27 (m, 1H), 5.48 (dq, J =
2.8Hz, J = 6.5Hz, 1H), 5.33-5.27 (m, 1H), 5.20 (d, 1H, J = 12.2Hz);
13
C NMR:  140.02,
132.62 (q,
3
J
C-F
=1.4 Hz), 129.47, 127.89, 124.19 (q,
1
J
C-F
= 282.4 Hz), 122.93 (q,
3
J
C-F

=1.1 Hz), 121.17, 81.33 (q,
2
J
C-F
= 33.1 Hz), 74.68;
19
F NMR:      d, J = 6.5 Hz,
3F)  HRMS (EI): m/z 188.0455, calculated for C
9
H
7
OF
3
   

1-Methyl-1-(trifluoromethyl)-1,3-dihydroisobenzofuran (2e)
1
H NMR:  7.43-7.29 (m, 3H), 7.29-7.23 (m, 1H), 5.20 (q, J = 12.2Hz, 2H), 5.20 (q, J =
1.1Hz, 3H);
13
C NMR:  139.91, 137.44, 129.27, 127.85, 125.57 (q,
1
J
C-F
= 286.0 Hz),
122.60, 121.08, 86.55 (q,
2
J
C-F
= 29.9 Hz), 73.72, 20.95;
19
F NMR:      HRMS (EI):
m/z 202.0619, calculated for C
10
H
9
OF
3
    
130

1,1-Bis(trifluoromethyl)-1,3-dihydroisobenzofuran (2f)

1
H NMR:  7.57-7.50 (m, 2H), 7.46-7.40 (m, 1H), 7.37-7.32 (m, 1H), 5.37 (s, 2H);
13
C
NMR:  140.56, 131.08, 129.55, 128.50, 123.80, 121.32, 122.33 (q,
1
J
C-F
= 287.5 Hz),
87.70 (quintet,
2
J
C-F
= 31.7 Hz), 76.02;
19
F NMR:      HRMS (EI): m/z 256.0309,
calculated for C
10
H
6
OF
6
    

1-(Difluoro(phenylsulfonyl)methyl)-1,3-dihydroisobenzofuran (2g)
1
H NMR:  8.02 (d, J = 7.6Hz, 2H), 7.78-7.71 (m, 1H), 7.63-7.57 (m, 2H), 7.43-7.36 (m,
2H), 7.35-7.25 (m, 2H), 6.01-5.90 (m, 1H), 5.22-5.11 (m, 2H);
13
C NMR:  140.39,
135.29, 133.70, 132.52, 130.75, 129.50, 129.17, 127.84, 123.47, 121.16, 120.65 (dd,
1
J
C-F

=289.6 Hz,
1
J
C-F
= 297.1 Hz), 80.61 (dd,
2
J
C-F
= 22.5 Hz,
2
J
C-F
= 28.5 Hz), 74.86;
19
F
NMR:  -107.97 (d, J = 242.8 Hz, 1F), -117.20 (dd, J = 20.8 Hz, J = 240.8 Hz, 1F)  

1-(Trifluoromethyl)isochroman (2h)
1
H NMR:  7.34-7.16 (m, 4H), 5.12 (q, J = 7.3Hz, 1H), 4.28-4.16 (m, 1H), 3.94-3.83 (m,
1H), 2.99-2.77 (m, 2H);
13
C NMR:  135.23, 128.96, 128.32, 127.61, 126.71 (q,
3
J
C-F
=
2.4 Hz), 126.51, 124.58 (q,
1
J
C-F
= 283.9 Hz), 73.13 (q,
2
J
C-F
= 30.3 Hz), 63.00, 28.47;
19
F
NMR:     (d, J = 7.3 Hz, 3F)   HRMS (EI): m/z 202.0616, calculated for
C
10
H
9
OF
3
    

131
1-Methyl-1-(trifluoromethyl)isochroman (2i)
1
H NMR:  7.38-7.31 (m, 1H), 7.30-7.21 (m, 2H), 7.19-7.13 (m, 1H), 4.20-4.11 (m, 1H),
3.98-3.88 (m, 1H), 2.87 (tdd, J = 5.2 Hz, J = 11.2Hz, J = 16.1Hz, 2H), 1.67 (q, J = 1.0Hz,
3H);
13
C NMR  134.87, 132.81, 128.97, 127.97, 126.64, 126.58 (q,
3
J
C-F
= 2.4 Hz),
125.89 (q,
1
J
C-F
= 287.2 Hz), 76.25 (q,
2
J
C-F
= 27.7 Hz), 61.47, 29.07, 23.27;
19
F NMR:
     HRMS (EI): m/z 216.0777, calculated for C
11
H
11
OF
3
    

1,1-Bis(trifluoromethyl)isochroman (2j)
1
H NMR:  7.66-7.60 (m, 1H), 7.41 (dt, J = 1.3 Hz, J = 7.5 Hz, 1H), 7.36-7.29 (m, 1H),
7.27-7.22 (m, 1H), 4.17 (t, J = 5.5 Hz, 2H), 2.93 (t, J = 5.5 Hz, 2H);
13
C NMR:  136.32,
129.78, 129.34, 127.23 (quintet,
3
J
C-F
= 2.8 Hz), 127.13, 123.80, 122.77 (q,
1
J
C-F
= 288.6
Hz), 77.22 (quintet,
2
J
C-F
= 29.3 Hz), 63.27, 28.56;
19
F NMR:  -78.68 (q, J = 8.9 Hz,
3F), -79.53 (q, J = 8.9 Hz, 3F)  HRMS (EI): m/z 270.0481, calculated for
C
11
H
8
OF
6
    

1-Phenyl-1-(trifluoromethyl)isochroman (2k)
1
H NMR:  7.57-7.46 (m, 3H), 7.39-7.25 (m, 5H), 7.24-7.19 (m, 1H), 4.09 (ddd, J = 3.3
Hz, J = 5.7 Hz, J = 11.1 Hz, 1H), 3.76 (dt, J = 3.9 Hz, J = 10.8 Hz, 1H), 3.12 (ddd, J =
5.8 Hz, J = 10.2 Hz, J = 16.1 Hz, 1H), 2.67 (dt, J = 3.6 Hz, J = 16.4 Hz, 1H);
13
C NMR: 
137.59, 135.13, 131.30, 129.62, 128.88, 128.65, 128.27, 127.90 (q,
3
J
C-F
=3.4 Hz) 125.99,
125.22 (q,
1
J
C-F
= 286.2 Hz), 80.96 (q,
2
J
C-F
= 27.9 Hz), 60.93, 28.58;
19
F NMR:
     HRMS (EI): m/z 278.0916, calculated for C
16
H
13
OF
3
    
132
1-Methyl-1-(trifluoromethyl)-1,3,4,5-tetrahydrobenzo[c]-oxep-ine (2l)
1
H NMR:  7.30-7.22 (m, 3H), 7.17-7.12 (m, 1H), 3.94-3.85 (m, 1H), 3.68-3.57 (m, 1H),
3.47-3.35 (m, 1H), 2.69-2.59 (m, 1H), 2.18-2.05 (m, 1H), 1.83-1.67 (m, 4H);
13
C NMR: 
139.88, 135.48, 130.88, 129.08, 128.73, 126.82, 125.68 (q,
1
J
C-F
= 285.6 Hz), 83.86 (q,
2
J
C-F
= 27.8 Hz), 61.29, 30.33 (q,
3
J
C-F
= 1.2 Hz), 27.80, 21.60;
19
F NMR:
     HRMS (EI): m/z 230.0915, calculated for C
12
H
13
OF
3
    















133
6.5 Chapter 6: Representative Spectra

Figure 6.2
1
H NMR Spectrum of 1a

134
Figure 6.3
19
F NMR Spectrum of 1a

135
Figure 6.4
1
H-
1
H COSY Spectrum of 1a

136
Figure 6.5 NOESY Spectrum of 1a

137
Figure 6.6
1
H-
19
F HOESY Spectrum of 1a






138
Figure 6.7
1
H NMR Spectrum of 2a


139
Figure 6.8
1
H-
1
H COSY Spectrum of 2a 


140
Figure 6.9 NOESY Spectrum of 2a

141
6.6 Chapter 6: References

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7. Dmowski, W.; Kaminski, M. J. Fluorine Chem. 1983, 23, 207.
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145
7 Chapter 7: Organocatalytic Stereoselective Conjugate
Addition of -Fluoro- -nitro-phenyl sulfonyl methane to -
Nitroolefins: The Construction of Fluorine-bearing Chiral
Carbon Center

7.1 Chapter 7: Introduction

The stereoselective construction of chiral organic molecules is one of the central
topics in modern organic chemistry.
1-2
Particularly, the asymmetric synthesis of organics
in a catalytic fashion is recognized as an efficient protocol in this field. Organocatalysis,
functioned by “pure” organic molecules, has been widely utilized in numerous
asymmetric reactions over the past few decades.
3-5
On the other hand, fluorine-containing
organic compounds are widely applied in medicinal chemistry and materials science due
to their exceptional biological and physical properties, such as enhanced metabolic
stability and high lipophilicity.
6-9
Therefore the synthesis of fluorinated chiral molecules,
mainly the asymmetric incorporation of stereogenic centers bearing fluorinated
functionalities, is of great interest.
10-11
Lately, the constructions of chiral carbon-fluorine
centers have attracted increasing attention, which is, however, found to be challenging.
12-
13
In principle this synthetic problem is usually tackled by asymmetric fluorination of a
carbon atom and formation of a C-C bond with a fluorine-bearing carbon atom. Although
the former strategy has been extensively employed, the latter approach still prevails due
to its wider applicability in the construction of fluorinated stereogenic centers in various
regimes.
14-18

The carbon-carbon bond formation reaction between nitroalkanes and nitroolefins
is of fundamental synthetic interests, nevertheless, the oligomerization of nitronate
146
anionic intermediates and nitroalkenes has been found as the major side reaction
undermining the efficiency of the transformation. This synthetic dilemma was recently
investigated by organocatalytic approaches in both racemic and stereoselective
fashions.
19-22
On the other hand, fluorinated sulfones have been developed by Prakash,
Hu, Shibata and many others as applicable reagents for the stereoselective introduction of
fluoromethyl functionalities in the organofluorine chemistry arena.
14,23-30
In particular,
the efficient conjugate addition of racemic FNSM to chalcone derivatives was found to
afford the corresponding adducts via a unique dynamic kinetic resolution (DKR) process
involving interconversion of enantiomeric pyramidal α-fluorocarbanions. Therefore it is
of both synthetic and theoretical interests to explore the asymmetric organocatalyst-
mediated conjugate addition of FNSM to nitroolefins for the construction of fluorinated
stereogenic center and the mechanistic aspects involved.

7.2 Chapter 7: Results and Discussion
Our group previously reported a highly efficient 1,4-addition of racemic α-fluoro-
α-nitro(phenylsulfonyl)methane (FNSM) to chalcones catalyzed by cinchona-based
catalysts.
14
In this work, we disclose the organocatalyzed conjugate addition of FNSM to
nitroolefins as part of our continuous efforts in stereoselective construction of fluorine-
containing chiral centers.
147
Ia Ib Ic Id
N
OH
N
N
OH
N
N
OH
N H
OMe
OMe
N
OH
N H
OMe
N
NHR
N
IIa, IIIa
N
NHR
N
N
NHR
N H
OMe
OMe
N
NHR
N H
OMe
IIb, IIIb
NH
S
F
3
C
F
3
C
IIc, IIIc IId, IIId
IIa-IId, R = H IIIa-IIId, R =
N
NH
N
OMe
N
H
S
N
NH
N
OMe
N
H
S
F
F
IV V VI
CF
3
N
NH
N
OMe
N
H
O
CF
3
HN
Ph
NH
Ph
S
HN
S
Me
2
N
O
O
CF
3
CF
3
NH
2
H
N N
NMe
2
N
H
S
H
N N
NMe
2
VII VIII
NH
2
NH
2
IX
H
N
HN
S
Me
2
N
CF
3
CF
3
X XI
N
H
CF
3
CF
3

Figure 7.1 Bifunctional organocatalysts
148
Hydrogen-bonding mediated organocatalysis has been extensively exploited in
asymmetric synthesis over the past decades.
31-33
We found that cinchona alkaloid-based
bifunctional catalysts
34-35
can promote the Michael addition of FNSM to chalcone
derivatives in good to excellent stereoselectivity. Based on this outcome, the study of the
conjugate addition between FNSM and nitroolefins was initially attempted by screening a
series of catalysts, including simple bifunctional catalysts I-III, VII and X (Figure 7.1),
as well as urea- and thiourea-based compounds III-VI, VIII, IX and XI (Figure 7.1).
The reaction was carried out in toluene with the catalysts, FNSM and (E)-β-nitrostyrene
in a ratio of 0.1:1:1.5. In general, the addition reaction underwent smoothly to afford the
Michael adduct in excellent yields under the reaction conditions. Due to the presence of
the phenylsulfonyl moiety, the deprotonation of FNSM is significantly faster than that of
the adduct, which substantially suppressed the previously mentioned oligomerization. On
the other hand, the best enantioselectivity was observed when IId was applied as the
catalyst (Table 7.1, entry 8). Differing from the addition of FNSM to chalcone
derivatives, although the diastereoselectivity was slightly increased, only unsatisfactory
enantiomeric excess was obtained when cinchona-based thiourea and urea catalysts were
exploited (Table 7.1, entries 9-15). Moreover, attempts to use the catalysts that were
particularly designed for the nitroalkane-nitroalkene addition
20,22
did not make significant
improvements in terms of stereoselectivity (Table 7.1, entries 17-20). Noticeably,
although quinidine and quinine derivatives have been found to exhibit
pseudoenantiomeric catalytic activity under many circumstances,
34-35
IIc was unable to
show any enantioselective activity indicating the complexity of the catalytic process
(Table 7.1, entries 7 and 8).
149
Table 7.1 Catalyst screening of asymmetric conjugate addition reaction of FNSM to
nitroolefins
Entry Catalyst Yield%
a
d.r.
b
ee%
c
1
2
3
4
5
6
7
8
>99 38:62 8
>99 41:59 9
>99 40:60 8
>99 28:72 7
>99
>99
>99
22
10
34:66 0
>99 26:74 57
Id
IIa
IIb
IIc
IId
Ic
9
IIIa
3 22:78 96
a.
19
F NMR yield; b. Determined by
19
F NMR; c. Determined by
chiral HPLC; d. Defluorination of V was observed; e. 5 mol%
catalyst was used.
(3a')
Ia
Ib
10
11
12
13
14
15
16
17
95 22:78 -5
91 20:80 4
95 23:77 6
97 26:74 14
97
96
>99
24:76 25
21:79 -15
28:72 5
>99 19:81 23
VII
VIII
IIId
18 IX
e
46 15:85 94
IIIb
IIIc
IV
V
d
VI
19 >99 44:56 37
X
20
XI
31 43:57 94
S NO
2
Ph
O O
F
Ph
NO
2
cat. 10 mol %
PhSO
2
Ph
1.5 eq
Toluene
+
1.0 eq Rac
1 2a 3a
F
O
2
N NO
2
(3a:3a')
38:62
37:63
12h
H
PhSO
2
H
3a'
F
O
2
N NO
2
Ph
+

150
Further investigation on the enhancement in the stereoselectivity was
concentrated on optimization of reaction parameters including temperature, as well as the
reaction media. A series of solvents, varying in polarities and coordination abilities, were
explored in the presence of catalytic amount of IId (Table 7.2, entries 1-13). It revealed
that the yields of the transformation were not significantly influenced by the medium,
however, both enantio- and diastereoselectivity were shown to be closely associated with
the solvents. On the other hand, there were no positive impacts associated with lowering
of the temperature.
Table 7.2 Screening of reaction media and temperature
PhSO
2
Ph
3a
F
O
2
N NO
2
H
PhSO
2
H
3a'
F
O
2
N NO
2
Ph
+
Entry
Yield%
a
d.r.
b
ee%
c
1
2
3
4
5
6
7
8
>99 26:74 57
>99
28:72 55 95
30:70 49 >99
41:59 52
>99
>99
>99
24
7
29:71 54
9
13 50:50
a.  and Et(30) are dielectric constants and solvatochromatic shifts of the solvents
(Kcal/mol), respectively; b.
19
F NMR yield; c. Determined by
19
F NMR; d.
Determined by chiral HPLC; d. The reactions were performed at -78
o
C for 3d.
3a'
10
11
12
30:70 46
54:46 30
>99 39:61 27
S NO
2
Ph
O O
F
Ph
NO
2
IId 10 mol %
Solvent, rt
+
Rac
1 2a
(3a:3a')
62:38
45:55
12h
Solvent ( /E
t
(30))
a
Toluene (2.37/33.9)
p-Xylene (2.27/33.1) 50:50 52
>99
72
85
>99
CH
2
Cl
2
(8.93/40.7)
CHCl
3
(4.71/39.1)
m-Xylene (2.54/-)
o-Xylene (2.35/-)
THF (7.43/37.4)
Et
2
O (4.24/34.5)
tBuOMe (-/34.7)
1,4-Dioxane (2.21/36.0)
Glyme (7.02/38.2)
Ethyl acetate (6.02/38.1) 13
ClC
2
H
4
Cl (10.1/39.4)
Toluene
d
14
15 CH
2
Cl
2
d
- 26:74
54:46 22
>99 43:57 25
35
98

151
The scope of this protocol has been investigated with a variety of nitroolefins
featuring different structural and electronic properties. The method was found to be
applicable to nitroolefins bearing both electron-withdrawing as well as electron-donating
groups to yield fluorinated 1,3-dinitro compounds in good to excellent yields (Table 7.3).
In general, the nitroolefins functionalized by electron-donating groups on the phenyl ring
afforded the products with slightly higher yields. The diastereomeric ratio of the protocol
was found to range from 45:55 to 76:24. On the other hand, low to moderate
enantiomeric excesses were achieved with the current protocol. In particular, the addition
between sterically hindered ortho-substituted nitroalkene and FNSM proceeds smoothly
to generate the adduct with moderate stereoselectivity in high yield (Table 7.3, entry 7).
152
Table 7.3 Organocatalyzed stereoselective conjugate addition between FNSM and
nitroolefins

Entry Yield (%)
a
d.r.
b
ee(%)
c
1
2
3
4
Nitroolefins
NO
2
NO
2
F
NO
2
Br
NO
2
94
(3a:3a') (3a/3a')
59:41
55:45
83 38:62
30/-
-/58
90
52/0
82 57:43 -/-
NO
2
Et
NO
2
MeO
NO
2
Br
5
6
7
52:48
37/- 76:24
47:53
99
94
96
S NO
2
Ph
O O
F
Ph
NO
2
IId
10 mol %
PhSO
2
Ph
1.5 eq
+
1.0 eq
Rac
1 2a 3a
F
O
2
N NO
2
12h
H
PhSO
2
H
3a'
F
O
2
N NO
2
Ph
+
CH
2
Cl
2
0/0
37/15
O
2
N
a.
19
F NMR yield; b. Determined by
19
F NMR; c. Determined by chiral HPLC.

153
It is worth noting that only moderate stereoselectivity was eventually achieved
despite extensive investigation and optimization of the reaction conditions. Therefore, it
would be of pragmatic and theoretical interest to investigate the mechanistic aspects of
the protocol as well.
Table 7.4 Kinetic analysis of the conjugate addition of FNSM/ClNSM to nitroolefins
S NO
2
Ph
O O
X
Ph
NO
2
Cat. 10 mol %
PhSO
2
Ph
+
F
O
2
N NO
2
293 K
H
PhSO
2
H
F
O
2
N NO
2
Ph
+
CH
2
Cl
2
r
addition
= 1.574X10
-4
[ClNSM][2] + 0.2996
r
addition
= 1.011X10
-5
[FNSM][2] + 0.1317
r
addition
= 4.161X10
-6
[FNSM][2] + 0.1249
Entry X
2
Rate Law
1
2
3
Catalyst
F
F
Cl
IId
Et
3
N
IId
Specific Rate
37.83
1.00
2.43

Entry 1
Time t (s) Conversion (%)
Concentration of starting
material [SM] (M)
1/[SM]
(1/M)
900 14 7.1638 0.1396
1800 20 6.664 0.1501
3600 29 5.9143 0.1691
5400 36 5.3312 0.1876
7200 41 4.9147 0.2035
9000 46 4.4982 0.2223
Entry 2
Time t (s) Conversion (%)
Concentration of starting
material [SM] (M)
1/[SM]
(1/M)
900 5 7.9135 0.1264
1800 9 7.5803 0.13194
3600 18 6.8306 0.14644
5400 18 6.8306 0.14644
7200 24 6.3308 0.1580
9000 26 6.1642 0.1622
Entry 3
Time t (s) Conversion (%)
Concentration of starting
material [SM] (M)
1/[SM]
(1/M)
900 75 2.0825 0.480
1800 80 1.666 0.600
3600 85 1.2495 0.800
5400 89 0.9163 1.091
7200 92 0.6664 1.501
9000 93 0.5831 1.715
154

Figure 7.2 Plot of [FNSM]
-1
/[ClNSM]
-1
versus reaction time

Our initial mechanistic studies focused on the kinetic nature of the reaction
through the measurement of overall reaction rates under standard catalytic conditions
employing the two substrates in equimolar amount.
1
H and
19
F nuclear magnetic
resonance (NMR) spectroscopy was utilized to monitor the conversion of the starting
materials. The reactions were performed in CD
2
Cl
2
to avoid the signal overlapping of
deuteriated toluene with the reaction contents in
1
H NMR spectra. The conjugate addition
between 1 and 2 promoted by Et
3
N and IId was found to exhibit a first order dependence
on both [FNSM] and [2] as 1/[FNSM] versus reaction time (t) was linear with R
2
values
155
of 0.9603 to 0.9990 (Table 7.4, entries 1 and 2, Figure 7.2). The kinetic data are also
consistent with the general proposal that FNSM and 2 participate in the transition states
of the catalysis with a molar ratio of 1:1. In particular, triethylamine has demonstrated a
higher catalytic activity as compared with IId, which can probably be attributed to the
weaker basicity of IId due to the existence of the primary amino group and its low steric
accessibility.
A similar rate law was also found in the addition of α-chloro-α-
nitro(phenylsulfonyl)methane (ClNSM) with 2 (Table 7.4, entry 3). Interestingly, the
substitution of chlorine for fluorine lead to a significant enhancement in the reaction rate
for the addition by a factor of about 40. This result contradicts an earlier study
36
on the
carbanion nucleophilicity of substituted dinitromethides toward methyl acrylate, which
has shown the addition of fluorinated dinitromethide to acrylate to be about 2000 times
faster than that of the chlorinated counterpart. It appears that current results cannot be
rationalized by the previous group state destabilization proposal
36
since the theoretical
calculations at the B3LYP/6-311+G(2d,p) level have revealed that (a) the ClNSM anion
has been found more stable than the fluorinated analogue by 5.8 kcal/mol in the gas phase
and (b) the anionic center on α-fluoro-α-nitro(phenylsulfonyl)methide is notably more
pyramidalized than that of the ClNSM anion (Figure 7.3).
37
Consequently, the high
polarizability
38
of ClNSM anion presumably plays a more critical role in the observed
elevated nucleophilicity, instead of its structural and thermodynamic properties.

156

Figure 7.3 Thermodynamics of deprotonation of FNSM and ClNSM and the optimized
geometris of ClNSM and FNSM anions

As a continuation of our previous work on the asymmetric conjugate addition of
racemic FNSM to chalcone, we theoretically investigated the KDR process by high level
quantum mechanical study. The ground state species and the transition state structures
(TS
1
, TS
2
and TS
3
) were computed as in the gas phase by DFT calculation at the
B3LYP/6-311+G(2d,p) and B3LYP/6-31+G(2d,p)//B3LYP/6-311+G(2d,p) levels,
respectively. The calculation revealed that the interconversion between the S- and R-
FNSM can undergo both anionic and enolic pathways. Although the interconversion
involving the FNSM anions seems to be thermodynamically quite unfavorable in
comparison with that of the enol, this pathway can still be one of the major interchange
route under the reaction régime since we have neglected solvation energies of the anions
and the tendency of forming ion pairs. Incorporation of these factors can significantly
decrease the energetic levels. As shown in Figure 7.4, the interconversion barrier from
(R)-FNSM anion to the neutral (S)-FNSM molecule is about 5.7 kcal/mol. According to
the calculation, the primary contribution to the interconversion barrier is the rotation
157
about the sulfur-fluorinated carbon bond. Noticeably, the barrier of inverting the absolute
configuration of the fluorinated carbon center was found to be fairly insignificant (ca. 0.5
kcal/mol), which contradicts with what is expected. In other words, the conversion from
the R-anion to its enantiomer, and vice versa, cannot proceed simply by inversion of the
anionic carbon. On the other hand, the enolic pathway was found to undertake TS
3
(with
C
s
symmetry) as the transition state with activation energy of 6.4 kcal/mol, comparable to
that of the anionic pathway.

Figure 7.4 Interconversion between (R)-FNSM and (S)-FNSM (The pathways from TS
1

and TS
3
to (S)-FNSM are omitted for clarity)

158
To gain deeper insight into the structural variation in the course of the
interconversions, a potential energy surface-like contour map was plotted in Figure 7.5.
The geometry of the species was defined by the dihedral angle of S-C
α
-N-F, indicating
the planarity and chirality of the fluorinated carbon, and the dihedral angle of C
β
-S-C
α
-F
that determines the facial accessibility of the anionic center. It has been shown that the
anions can interconvert along the red curve as a cyclic process, and the enols interchange
through the planar transition state (TS
3
) primarily by the rotation about the S-C
α
bond
(the blue curve). Apparently, the change of the stereogenic carbons of the two FNSM
isomers can only occur through enolic or anionic pathways with barriers of 5-6 kcal/mol
relative to the anions or the enol. Since both enols and anions are known to be the key
intermediates in the addition reaction, we assumed that the crucial structures participating
in the transition states of the addition can be located in the grey regions. Based on these
results, we have proposed a mechanistic scenario of the conjugate addition of racemic
FNSM to nitroolefins. It is clear that the stereoselectivity of the addition reaction is not
only dependent on the facial discrimination of nitroolefins arising from its interactions
with the catalyst, but also closely associated with the deracemization of FNSM. As
demonstrated, the application of the catalysts particularly designed for the conjugate
addition of nitroalkanes to nitroalkenes, afforded the products in lower enantioselectivity
and similar diastereoselectivity when compared with literature results.
20,22
It suggests that
the critical factor in determining stereoselectivity is the deracemization rate of FNSM
instead of the facial selectivity of the nitroolefins. Since the current reaction was found to
be significantly faster than the reported protocols,
14,20,22
the activation energy of the
addition is supposed to be low, which may presumably be comparable with that of the
159
deracemization. Under this circumstance, the R and S intermediates were not likely to be
in thermodynamic equilibrium during the course of the transformation, which results in
the observation of low enantioselectivity.

Dihedral Angle (S-C -N-F)

Figure 7.5 Structural changes in the interconversion between (R)- and (S)-FNSM

7.3 Chapter 7: Conclusion
We have developed a stereoselective protocol for the synthesis of 1,3-dinitro
compounds bearing a stereogenic fluorinated carbon center. This synthetic approach
demonstrates a chemically efficient method, which can afford the adducts in low to
moderate stereoselectivity. Importantly, exhaustive mechanistic investigation has been
160
performed in order to rationalize the reaction, including the kinetics properties and the
detailed KDR pathway. The study on the interconversion of the key intermediates has
provided an informative insight into the KDR process of both asymmetric fluorinated and
non-fluorinated carbanions functionalized by the phenyl sulfonyl motif.

7.4 Chapter 7: Experimental
7.4.1 General
Unless otherwise mentioned, all other reagents were purchased from commercial
sources. Catalysts I-XI were prepared according to the reported procedure.
14
Column
chromatography was performed using silica gel (60-200 mesh). Analytical thin-layer
chromatography (TLC) was performed on precoated, glass-backed silica gel.
1
H,
13
C and
19
F NMR spectra were recorded on 400 MHz Varian NMR spectrometer.
1
H NMR
chemical shifts were determined relative to (CH
3
)
4
Si (TMS) as internal standard at δ 0.0
or to the signal of a residual protonated solvent CDCl
3
as internal standard at δ 7.26.
13
C
NMR chemical shifts were determined relative to TMS as internal standard at δ 0.0 or to
the
13
C signal of solvent CDCl
3
as internal standard at δ 77.16.
19
F NMR chemical shifts
were determined relative to CFCl
3
as internal standard at δ 0.0. HPLC analysis was
carried out on ChiralCel OD-H or ChiralPak AD-H columns.

161
7.4.2 Typical procedure for the preparation of
(chloro(nitro)methylsulfonyl)benzene

PhSO
2
CH
2
Cl (1.86 g, 10 mmol) and isobutyl nitrate (1.34 mL, 11 mmol) were
dissolved in anhydrous THF (50 mL) in a 100 mL Schlenk flask under Ar. The solution
was cooled to -78
o
C. KHMDS (33 mL, 0.91M, 30 mmol) added dropwise to the Schlenk
flask. The reaction mixture was stirred for 30 min at the same temperature before poured
into 4M HCl aqueous solution (100 mL). The resultant mixture was washed with water
and was extracted with CH
2
Cl
2
(50 mL  3). The combined organic layer was dried over
MgSO4, and the solvent was evaporated. The mixture was purified by column
chromatography with silica gel to afford a crystalline solid (1.37g, 58%).
1
H NMR
(CDCl
3
) δ 7.97 (ddd, J = 8.0, 2.1, 1.2 Hz, 2H), 7.85 (tt, J = 8.0, 1.2 Hz, 1H), 7.70 – 7.65
(m, 2H), 6.59 (s, 1H).
13
C NMR (CDCl
3
) δ 136.6, 131.7, 131.3, 129.8, 98.9. HRMS:
calcd for C
7
H
5
ClNO
4
S
-
233.9633 (M-H
-
) found: m/z 233.9632.

7.4.3 Typical procedure for catalytic conjugate addition of α-fluoro-α-
nitro(phenylsulfonyl)methane to nitroolefins

PhSO
2
Ar
F
O
2
N NO
2 S NO
2
Ph
O O
F
Ar
NO
2
70% Et
3
N
CH
2
Cl
2
, rt, 12h
+
1eq 1.5eq

To a solution of α-fluoro-α-nitro(phenylsulfonyl)methane (21.9 mg, 0.1 mmol, 1
equivalent) and nitroolefins (0.15 mmol, 1.5 equivalent) in CH
2
Cl
2
, Et
3
N (10.0 µL 0.1
mmol, 0.7 equivalent) was added. The reaction mixture was stirred for 12 h at room
162
temperature and the conversion was monitered by
19
F NMR before purification. The
reaction mixture was purified by flash chromatography.
7.4.4 Typical procedure for catalytic enantioselective conjugate addition of α-
fluoro-α-nitro(phenylsulfonyl)methane to nitroolefins

PhSO
2


Ar
F
O
2
N NO
2
S NO
2
Ph
O O
F
Ar
NO
2
IId 10 mol %
CH
2
Cl
2
, rt
+
Rac
12h
1eq. 1.5eq

To a solution of α-fluoro-α-nitro(phenylsulfonyl)methane (21.9 mg, 0.1 mmol, 1
equivalent) and nitroolefins (0.15 mmol, 1.5 equivalent) in CH
2
Cl
2
(0.5 mL), catalyst IId
was added (3.2 mg 0.01 mmol, 10 mol%) in one load. The reaction mixture was
monitored by
19
F NMR for conversion and diastereoselectivity, and purified by flash
column chromatography to produce the title product in good to excellent yield.
7.4.5 Spectral Data
(1-fluoro-1,3-dinitro-2-(4-nitrophenyl)propylperoxy)(phenyl)sulfane (Table 7.3,
entry 1)
1
H NMR δ 8.18-8.11 (m, 3H), 7.85 (d, J=7.4Hz, 2H), 7.81-7.74 (m, 3H), 7.71 (d, J = 8.5
Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.52 (t, J=8.0Hz, 2H), 7.48-7.42 (m, 4H), 5.62 (dd,
J=3.8Hz, J=14.2Hz, 1H), 5.33 (ddd, J=3.8Hz, J=11.5Hz, J=29.3Hz, 1H), 5.22-5.02 (m,
3H), 4.94 (dd, J=11.6Hz, J=14.2Hz, 1H).
13
C NMR δ 148.88, 148.82, 137.28, 136.98,
136.33, 135.65, 130.84, 130.58, 130.41, 130.16, 130.05, 129.86, 122.18 (d, J = 290.6Hz),
73.69 (d, J = 2.4 Hz), 73.67 (d, J = 3.2Hz), 45.36 (d, J = 19.3Hz), 44.76 (d, J = 16.1Hz),
29.69.
19
F NMR δ -119.02 (d, J = 17.5 Hz, 1F), -129.46 (d, J=29.3 Hz, 1F).
163
(1-fluoro-2-(4-fluorophenyl)-1,3-dinitropropylperoxy)(phenyl)sulfane (Table 7.3,
entry 2)
1
H NMR δ 7.87-7.82 (m, 2H), 7.78-7.73 (m, 1H), 7.73-7.67 (m, 1H), 7.67-7.62 (m, 2H),
7.60-7.54 (m, 2H), 7.52-7.44 (m, 2H), 7.24-7.19 (m, 2H), 7.18-7.14 (m, 2H), 6.98-6.91
(m, 4H), 5.54 (dd, J=3.9Hz, J=13.8Hz, 1H), 5.24-5.07 (m, 2H), 5.05-4.94 (m, 2H), 4.89
(dd, J=11.6Hz, J=13.6Hz, 1H).
13
C NMR δ 163.59 (d, J=251.1Hz), 163.47 (d, J =
251.0Hz), 137.00, 136.54, 131.54 (dd, J=1.4Hz, J = 8.6Hz), 131.22, 131.14 (d, J =
7.5Hz), 130.78, 130.75 (d, J = 1.3Hz), 130.65, 129.92, 129.66, 125.08 (d, J = 3.5Hz),
124.35 (d, J = 3.5Hz), 122.72 (d, J = 289.8Hz), 121.62 (d, J = 283.7Hz), 116.69 (d, J =
22.0Hz), 116.63 (d, J = 21.9Hz), 74.30 (d, J =3.9Hz), 74.19 (d, J = 2.6Hz), 45.35 (d, J =
19.5Hz), 44.64 (d, J = 16.1Hz).
19
F NMR δ -109.86 - -109.96(m, 1F), -109.99- -110.09
(m, 1F), -118.63 (d, J = 17.4 Hz, 1F), -130.04 (d, J = 30.0 Hz, 1F).
(2-(4-bromophenyl)-1-fluoro-1,3-dinitropropylperoxy)(phenyl)sulfane (Table 7.3,
entry 3)
1
H NMR δ 7.94-7.89 (m, 2H), 7.86-7.75 (m, 2H), 7.73-7.67 (m, 2H), 7.67-7.61 (m, 2H),
7.59-7.53 (m, 2H), 7.49-7.42 (m, 4H), 7.19-7.09 (m, 4H), 5.61 (dd, J=3.9Hz, J=13.9Hz,
1H) 5.29-5.12 (m, 2H), 5.10-4.99 (m, 2H), 4.94 (dd, J=11.6Hz, J=13.8Hz, 1H).
19
F NMR
δ -118.65 (d, J = 17.5 Hz, 1F), -129.80 (d, J=29.9 Hz, 1F).
(1-fluoro-1,3-dinitro-2-phenylpropylperoxy)(phenyl)sulfane (Table 7.3, entry 4)
1
H NMR δ 7.88-7.83 (m, 2H), 7.78-7.72 (m, 1H), 7.60-7.54 (m, 2H), 7.29-7.20 (m, 5H),
5.55 (dd, J=3.8Hz, J=13.7Hz, 1H) 5.17 (ddd, J=3.8Hz, J=11.5Hz, J=30.3Hz, 1H) 4.93
(dd, J=11.5Hz, J=13.5Hz, 1H).
13
C NMR δ 136.92, 130.79, 130.69, 130.11, 129.89,
164
129.45, 129.23, 129.16, 122.83 (d, J=289.8Hz), 74.21 (d, J=2.6Hz), 45.21 (d, J=15.8Hz).
19
F NMR δ -129.66 (d, J = 30.2 Hz, 1F).
1
H NMR δ 7.72-7.59 (m, 3H), 7.50-7.42 (m, 2H), 7.34-7.20 (m, 3H), 7.18-7.13 (m, 2H),
5.22-5.16 (m, 1H), 5.08-4.92 (m, 2H).
13
C NMR δ 136.41, 131.21, 130.78 (d, J=1.3Hz),
130.13, 129.61, 129.58 (d, J=1.2Hz), 129.45, 128.52, 121.69 (d, J=284.4Hz), 74.36 (d,
J=4.0Hz), 45.97 (d, J=19.7Hz).
19
F NMR δ -117.76 (d, J = 16.6 Hz, 1F).
(2-(4-ethylphenyl)-1-fluoro-1,3-dinitropropylperoxy)(phenyl)sulfane (Table 7.3,
entry 5)
1
H NMR δ 7.92 (d, J = 7.9Hz, 2H), 7.84-7.79 (m, 1H), 7.63 (t, J = 8.0Hz, 2H), 7.21-7.09
(m, 4H), 5.59 (dd, J = 3.8Hz, J = 13.7Hz, 1H) 5.20 (ddd, J = 3.8Hz, J = 11.5Hz, J =
30.4Hz, 1H), 4.98 (dd, J = 11.5Hz, J = 13.6Hz, 1H), 2.58 (q, J = 7.6Hz, 2H), 1.17 (t, J =
7.6Hz, 3H).
13
C NMR δ 146.27, 136.87, 130.77, 129.87, 129.05, 128.92, 126.21, 122.94
(d, J = 289.7 Hz), 74.29 (d, J = 2.7Hz), 44.95 (d, J=15.9 Hz), 28.39, 14.93.
19
F NMR δ -
129.71 (d, J = 30.4 Hz, 1F).
(1-fluoro-2-(4-methoxyphenyl)-1,3-dinitropropylperoxy)(phenyl)sulfane major
isomer (Table 7.3, entry 6)
1
H NMR (400 MHz, CDCl
3
): δ 7.79-7.68 (m, 3H), 7.58-7.50 (m, 2H) 7.14 (d, J = 8.8Hz,
2H), 6.84-6.79 (m, 2H), 5.20 (dd, J = 3.0Hz, J = 13.3Hz, 1H) 5.10-4.94 (m, 2H), 3.79 (s,
3H).
13
C NMR (100.63 MHz, CDCl
3
): δ 160.79, 136.31, 131.40, 130.78 (d, J = 6.8Hz),
129.54, 121.83 (d, J = 283.7Hz), 119.90, 114.81, 74.45 (d, J = 4.0Hz), 55.31, 45.45 (d, J
= 19.6Hz).
19
F NMR δ -118.73 (d, J = 17.3Hz, 1F).

165
(2-(2-bromophenyl)-1-fluoro-1,3-dinitropropylperoxy)(phenyl)sulfane (Table 7.3,
entry 7)
1
H NMR δ 7.90 (d, J=7.5Hz, 3H), 7.81-7.73 (m, 2H), 7.64-7.56 (m, 4H), 7.53 (dd,
J=1.4Hz, J=7.9Hz, 1H), 7.49 (dd, J=1.3Hz, J=8.1Hz, 1H), 7.36-7.31 (m, 1H), 7.27-7.08
(m, 5H), 6.98 (dd, J=1.5Hz, J=7.8Hz, 1H) 5.93 (ddd, J=3.9Hz, J=11.0Hz, J=29.4Hz, 1H),
5.77-5.67 (m, 1H), 5.66-5.57(m, 1H), 5.54 (dd, J=4.0Hz, J=13.7Hz, 1H), 5.08 (dd,
J=10.8Hz, J=14.5Hz, 1H), 4.86 (dd, J=11.0Hz, J=13.7Hz, 1H).
13
C NMR δ 137.00,
136.85, 134.45, 134.23, 131.39, 131.36, 131.17, 131.16, 131.02, 130.73, 130.54, 129.99,
129.93, 129.15 (d, J = 1.4Hz), 128.67, 128.48, 128.28 (d, J=3.9Hz), 127.51, 127.43,
126.64, 121.97 (d, J=290.1Hz), 120.51 (d, J=282.4Hz), 74.66 (d, J=4.4Hz), 74.55 (d,
J=4.0Hz), 43.70 (d, J=21.2Hz), 42.84 (d, J=15.6Hz).
19
F NMR δ -114.91 (d, J = 6.3 Hz,
1F), -128.95 (d, J=29.4 Hz, 1F).
(1-chloro-1,3-dinitro-2-phenylpropylperoxy)(phenyl)sulfane (Table 7.4, entry 3)
1
H NMR δ 7.99-7.93 (m, 2H), 7.88-7.78 (m, 1H), 7.70-7.59 (m, 2H), 7.38-7.27 (m, 5H),
5.58 (dd, J=3.1Hz, J=14.2Hz, 1H), 5.37 (dd, J=3.1Hz, J=11.2Hz, 1H), 5.04 (dd,
J=11.7Hz, J=13.3Hz, 1H).
13
C NMR δ 136.73, 131.53, 130.84, 130.10, 129.97, 129.71,
129.49, 129.23, 118.95, 75.58, 47.42.
166
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Asset Metadata

Creator Do, Clement (author)

Core Title Multicomponent synthesis of fluorinated organic compounds using novel lewis acid catalysis and related chemistry

Contributor Electronically uploaded by the author (provenance)

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 08/02/2010

Defense Date 06/23/2010

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag Ga(OTf)3,Lewis acid catalysis,OAI-PMH Harvest,organofluorine

Language English

Advisor Prakash, G.K. Surya (committee chair), Olah, George A. (committee member), Shing, Katherine S. (committee member)

Creator Email clementdo@gmail.com,clementdo@yahoo.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m3253

Unique identifier UC182530

Identifier etd-Do-3958 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-369717 (legacy record id),usctheses-m3253 (legacy record id)

Legacy Identifier etd-Do-3958.pdf

Dmrecord 369717

Document Type Dissertation

Rights Do, Clement

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email uscdl@usc.edu

Abstract (if available)

Abstract This dissertation focuses on the development of new methodologies for the synthesis of both fluorinated and non-fluorinated biologically important molecules via the use of green Lewis acid catalysts. It also describes the syntheses of fluorinated cyclic ethers via Mitsunobu conditions. In addition, the stereoselective construction of fluorine bearing chiral carbon centers have also been explored.